Sirtuins and NAD+ in the Development and Treatment of Metabolic and Cardiovascular Diseases

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Sirtuins 和 NAD + 在代谢和心血管疾病发生和治疗中的作用

Alice E. Kane 爱丽丝 · e · 凯恩, and ,及David A. Sinclair 大卫 · a · 辛克莱Originally published 最初出版13 Sep 2018 二零一八年九月十三日https://doi.org/10.1161/CIRCRESAHA.118.312498Circulation Research. 2018;123:868–885 《循环研究》2018; 123:868-885

Abstract

摘要

The sirtuin family of nicotinamide adenine dinucleotide–dependent deacylases (SIRT1–7) are thought to be responsible, in large part, for the cardiometabolic benefits of lean diets and exercise and when upregulated can delay key aspects of aging. SIRT1, for example, protects against a decline in vascular endothelial function, metabolic syndrome, ischemia-reperfusion injury, obesity, and cardiomyopathy, and SIRT3 is protective against dyslipidemia and ischemia-reperfusion injury. With increasing age, however, nicotinamide adenine dinucleotide levels and sirtuin activity steadily decrease, and the decline is further exacerbated by obesity and sedentary lifestyles. Activation of sirtuins or nicotinamide adenine dinucleotide repletion induces angiogenesis, insulin sensitivity, and other health benefits in a wide range of age-related cardiovascular and metabolic disease models. Human clinical trials testing agents that activate SIRT1 or boost nicotinamide adenine dinucleotide levels are in progress and show promise in their ability to improve the health of cardiovascular and metabolic disease patients.

Sirtuin 家族依赖烟酰胺腺嘌呤二核苷酸的脱酰基酶(SIRT1-7)被认为在很大程度上负责精益饮食和锻炼的心血管代谢的好处,当上调可以延缓衰老的关键方面。例如,SIRT1可以防止血管内皮功能下降、代谢症候群、缺血-再灌注损伤、肥胖和心肌病,而 SIRT3可以防止血脂异常和缺血-再灌注损伤。然而,随着年龄的增长,烟酰胺腺嘌呤二核苷酸水平和去乙酰化酶活性稳步下降,而肥胖和久坐不动的生活方式进一步加剧了这种下降。Sirtuins 或烟酰胺腺嘌呤二核苷酸的激活可以诱导血管生成,胰岛素敏感性,以及其他一系列与年龄相关的心血管和代谢疾病模型的健康益处。激活 SIRT1或提高烟酰胺腺嘌呤二核苷酸水平的人体临床试验测试试剂正在进行中,并显示出改善心血管和代谢疾病病人健康状况的潜力。https://remarqable.com/web/topwidget.html

The lifespan extending abilities of the sirtuins were first discovered in yeast in the 1990s1,2 when the silent information regulator (SIR2) gene was shown to increase the replicative lifespan of yeast when upregulated.2 Sir2 is a yeast gene silencing protein, which silences transcription at the HM mating-type loci in young yeast but relocalizes to the ribosomal DNA as cells age to prevent DNA damage that contributes to yeast aging.3 Upregulating the expression of Sir2 reduces DNA damage and increases the lifespan of yeast.2 Subsequently, Sir2 was shown to have histone deacetylase activity that requires nicotinamide adenine dinucleotide (NAD),4,5 and sirtuins in mammals (SIRT1–7) were identified. Mammalian sirtuins were also shown to have important beneficial roles in aging, longevity, and stress responses.6–8Increasing the activity of the sirtuins is associated with the delay of age-related diseases9–13 and, in some cases, increased longevity.14–17

沉默信息调节因子 SIR2(silent information regulator,SIR2)基因上调后可以延长酵母的复制寿命,这是在20世纪90年代首次在酵母中发现 SIR2具有延长寿命的能力。2 Sir2是一种酵母基因沉默蛋白,它在年轻酵母的 HM 交配型位点沉默转录,但随着细胞年龄的增长,重新定位到核糖体 DNA,以防止 DNA 损伤导致酵母衰老。3上调 Sir2的表达可以减少 DNA 损伤,延长酵母的寿命。2随后,Sir2被证明具有组蛋白脱乙酰酶活性,这需要哺乳动物的烟酰胺腺嘌呤二核苷酸(NAD)、4,5和去乙酰化酶(SIRT1-7)。哺乳动物去乙酰化酶也被证明在衰老、长寿和应激反应中有重要的作用。6-8去乙酰化酶活性的增加与年龄相关疾病的延迟有关,在某些情况下,可延长寿命

Mammalian sirtuins are NAD+-dependent deacylases with a huge range of roles in transcription regulation, energy metabolism modulation, cell survival, DNA repair, inflammation, and circadian rhythm regulation.8,18 SIRT1 which is the most extensively studied sirtuin is found in the nucleus and cytosol and along with histone deacetylation also modulates transcription factors, such as p53,19 nuclear factor κ-light-chain-enhancer of activated B cells (NFκB),20 forkhead box (FOXOs)21 and peroxisome proliferator-activated receptor γ coactivator 1-α (PGC1α),22 and DNA repair proteins, such as poly ADP-ribose polymerase 1 (PARP1).23 SIRT2 is a cytosolic sirtuin while SIRT3, 4, and 5 are located in the mitochondria and have roles in oxidative stress and lipid metabolism.24–26 SIRT6 and 7 are nuclear sirtuins with roles in gene expression and DNA repair.27,28 There is growing evidence that sirtuins, along with deacetylation, also have roles in catalyzing other reactions, such as demalonylation, desuccinylation, and mono-ADP-ribosylation,29,30 collectively termed deacylase reactions.


哺乳动物去乙酰化酶是 NAD + 依赖的去乙酰化酶,在转录调节、能量代谢调节、细胞存活、 DNA 修复、炎症和昼夜节律调节等方面有着广泛的作用。8,18 SIRT1是目前研究最广泛的 sirtuin 蛋白,主要存在于细胞核和细胞质中,并且与组蛋白去乙酰化一起调节转录因子,如活化 b 细胞的 p53,19核因子轻链增强子(nf b),20叉头盒(FOXOs)21和过氧化物酶体增殖物活化受体辅激活因子1-(pgc1)、22和 DNA 修复蛋白,如多聚 ADP-ribose 聚合酶1(PARP1)。23 SIRT2是一种细胞溶性 sirtuin,而 SIRT3、4和5位于线粒体中,在氧化应激和脂质代谢中起作用。24-26 SIRT6和7是参与基因表达和 DNA 修复的核 sirtuins。有越来越多的证据表明,去乙酰化连同去乙酰化一起,也在催化其他反应中起作用,如去孤立化、去 uccinylation 和单 adp- 核糖基化,29,30统称为脱酰化反应。

The activity of SIRT1 can be increased with pharmaceuticals known as sirtuin-activating compounds (STACs). One of the first STACs, resveratrol, was discovered in a screen for molecules that increased the activity of human SIRT1 and extended the lifespan of yeast.31 Since then, there have been several generations of STACs with increasing potency and specificity, including SRT1720 and SRT2104.6,9,32 STACs act as allosteric activators of SIRT1, binding to the STAC-binding domain in the N terminus and via a bend-at-the-elbow model increasing the binding affinity of a substrate for SIRT1.33,34 Whether STACs activate sirtuins other than SIRT1 and the mechanism of this activation is still not completely understood.35 In addition to SIRT1, resveratrol has been reported to activate SIRT336 and SIRT5,37 as well as nonsirtuin targets.38,39 Honokiol is believed to be primarily a SIRT3 activator40,41 although it may also activate SIRT1.42,43 Sirtuin transgenic mice should be used in combination with STACs to confirm the roles of individual sirtuins in mechanistic studies.

SIRT1的活性可以通过已知的去乙酰化酶激活化合物(STACs)来增强。第一批 STACs 中的一种,白藜芦醇,是在一个增加人类 SIRT1活性和延长酵母寿命的分子筛选中发现的。31从那时起,已经有几代 STACs 具有增强的效力和特异性,包括 SRT1720和 SRT2104.6,9,32 STACs 作为 SIRT1的变构激活剂,在 n 端结合 stag 结合域,并通过弯曲肘部模型增加 SIRT1.33,34的结合亲和力,STACs 是否激活 SIRT1以外的基质异性。35除 SIRT1外,据报道白藜芦醇还能激活 SIRT336和 SIRT5,37以及非去乙酰化酶靶点。38,39 Honokiol 被认为主要是 SIRT3激活剂40,41虽然它也可能激活 SIRT1.42,43 Sirtuin 转基因小鼠应与 STACs 联合使用,以确认个别 Sirtuin 在机制研究中的作用。

For almost a century, NAD+ has been known as a fundamental housekeeping molecule that catalyzes electron transfer in metabolic reduction-oxidation reactions. In the past 10 years, NAD+ has also emerged as a key modulator of cell signaling and survival pathways.7,44 The discovery that NAD+ is an essential substrate of sirtuin deacetylation created renewed interest in NAD+ as a potential modulator of longevity and health. The sirtuin deactylation reaction involves the removal of an acetyl group from target substrates via the conversion of NAD+ to nicotinamide and O-acetyl-ADP-ribose4,30 (Figure 1).


近一个世纪以来,NAD + 一直被认为是一种基本的内务分子,能够催化电子转移在代谢/氧化还原反应反应中的作用。在过去的10年中,NAD + 已经成为细胞信号转导和生存途径的关键调节剂。7,44 NAD + 是去乙酰化的重要底物这一发现使人们对 NAD + 作为一种长寿和健康的潜在调节剂重新产生了兴趣。去乙酰化反应包括通过 NAD + 转化为烟酰胺和 o- 乙酰 -adp-ribose4去除靶基质上的乙酰基(图1)。

Figure 1.
Figure 1. Synthesis, salvage, and metabolism of nicotinamide adenine dinucleotide (NAD+). NAD+ supplies in the body come from either de novo synthesis or via salvage pathways. NAD+ is synthesized de novo from dietary tryptophan via a series of enzymatic reactions ultimately resulting in the production of nicotinic acid adenine dinucleotide (NAAD), which is converted to NAD+ by NAD synthase. However, in the heart, the vast majority of NAD+ is synthesized via salvage routes from nicotinamide (NAM), nicotinamide riboside (NR), and nicotinic acid (NA). NAM and NR are converted to nicotinamide mononucleotide (NMN) by nicotinamide phosphoribosyltransferase (NAMPT) and nicotinamide riboside kinases (NRKs), respectively. NMN is then converted to NAD+ by nicotinamide mononucleotide adenylyltransferease (NMNAT) 2 in the cytoplasm, NMNAT3 in the mitochondria, and NMNAT1 in the nucleus. NA is converted, via a series of reactions into NAAD and finally to NAD+ by NAD synthase. NAD+ is a necessary substrate of sirtuin deacetylation reactions, by which it is converted into NAM. NAD+ is broken down by sterile α and TIR motif–containing protein 1 (SARM1), cluster of differentiation 38 (CD38), poly ADP-ribose polymerase 1 (PARP1), and SIRTS1–7. SIRTs 3, 4, and 5 are located in the mitochondria, SIRT 2 is located in the cytoplasm, SIRT6 and 7 are found in the nucleus, and SIRT1 is found in both the cytoplasm and nucleus. Sirtuins and NAD+ have a variety of roles in cardiac and vascular cells that can effect cardiovascular function. For example, SIRT3 acts to block opening of the mitochondrial permeability transition pore (mPTP) to reduce cell swelling and hypertrophy. Figure made using adapted images from http://smart.servier.com.图1。烟酰胺腺嘌呤二核苷酸的合成、回收和新陈代谢。体内的 NAD + 供应来自从头合成或者通过补救途径。NAD + 是由膳食色氨酸经一系列酶促反应从头合成的,最终产生烟酸腺嘌呤二核苷酸(NAAD) ,然后通过 NAD 合成酶将其转化为 NAD + 。然而在心脏方面,绝大多数 NAD + 的合成是通过烟酰胺(NAM)、烟酰胺核苷(NR)和烟酸(NA)的打捞路线进行的。烟酰胺磷酸核糖基转移酶(NAMPT)和烟酰胺核糖苷激酶(NRKs)分别将 NAM 和 NR 转化为烟酰胺单核苷酸(NMN)。NMN 在细胞质中被烟酰胺单核苷酸腺病毒转化为 NAD + ,在线粒体中被转化为 NMNAT3,在细胞核中被转化为 NMNAT1。NA 通过一系列反应转化为 NAAD,最后通过 NAD 合酶转化为 NAD + 。NAD + 是 sirtuin 脱乙酰化反应的必需底物,通过它可以转化为 NAM。NAD + 通过不育和含有 TIR 基序的蛋白1(SARM1)、分化簇38(CD38)、多聚 adp 核糖聚合酶1(PARP1)和 SIRTS1-7进行分解。Sirt3、4、5位于线粒体内,sirt2位于细胞质内,SIRT6、7位于细胞核内,SIRT1位于细胞质和细胞核内。Sirtuins 和 NAD + 在心脏和血管细胞中有多种作用,可以影响心血管功能。例如,SIRT3作用于阻断线粒体通透性转换孔(mPTP)的开放,以减少细胞肿胀和肥大。图片来源于 http://smart.servier.com 的改编图片。

The first evidence that NAD+ boosting was beneficial to health came from yeast studies. Overexpression of yeast PNC1, which encodes a nicotinamidase that catalyzes the first step in the NAD+ salvage pathway, increased stress resistance and lifespan of yeast cells by mimicking caloric restriction.46 Increasing age is associated with significantly reduced levels of NAD+,47 which is coupled with an increase in NADH,48,49 suggesting that reduction-oxidation imbalance may contribute to decreased NAD+ with aging. Increasing NAD+ levels, especially in old age, is associated with a range of beneficial health effects in a variety of models.7,45

促进 NAD + 对健康有益的第一个证据来自酵母菌的研究。过度表达的酵母 PNC1,编码烟酰胺酶,催化 NAD + 挽救路径的第一步,通过模仿热量限制增加酵母细胞的抗压力和寿命。增加 NAD + 水平,特别是在老年,与一系列有益的健康影响,在各种模式。7,45

NAD+ supplies in the cells are replenished by either de novo synthesis from dietary tryptophan or via salvage pathways from precursors including nicotinamide, nicotinamide riboside (NR), and nicotinic acid50 (Figure 1). In the heart, >99% of NAD+ is synthesized via the salvage pathway.51 Levels of NAD+ can be raised by providing precursors to NAD+ such as NR, nicotinamide, or nicotinamide mononucleotide (NMN) or by increasing the levels of enzymes involved in the NAD+synthesis pathways, such as nicotinamide phosphoribosyltransferase (NAMPT).52 Another potential approach is to inhibit enzymes that consume NAD+ including cluster of differentiation 38 (CD38),53–55 SARM1 (sterile α and TIR motif–containing protein 1),56,57 and PARP1.58

细胞中的 NAD + 补给可以通过膳食色氨酸中的从头合成或者烟酰胺、烟酰胺核糖苷(NR)和烟酸50等前体的补救途径来补充。51 NAD + 的水平可以通过提供 NAD + 的前体,如 NR、烟酰胺或烟酰胺单核苷酸(NMN)或通过提高 NAD + 合成途径中涉及的酶的水平,如烟酰胺磷酸核糖转移酶(NAMPT)来提高。52另一种潜在的方法是抑制消耗 NAD + 的酶,包括分化簇38(CD38)、53-55 SARM1(以及含有 TIR 基序的蛋白质1)、56、57和 par1.58

As described below, the sirtuins and NAD+ have major roles in maintaining homeostasis of metabolic processes and cardiovascular function, which are disturbed in aging and in cardiovascular and metabolic diseases. The manipulation of sirtuins and NAD+ could lead to radical new medicines to prevent and treat these and other age-related diseases.

如下所述,去乙酰化酶和 NAD + 在维持代谢过程和心血管功能的稳态方面发挥着重要作用,这些过程和功能在衰老和心血管及代谢疾病中受到干扰。去乙酰化酶和 NAD + 的操纵可能导致激进的新药物,以预防和治疗这些和其他与年龄有关的疾病。

Sirtuins and NAD+ in Age-Related Cardiovascular and Metabolic Diseases

Sirtuins 和 NAD + 与年龄相关的心血管和代谢疾病

Loss of sirtuin activity and NAD+ levels with age are implicated in the pathogenesis of a wide variety of cardiovascular and metabolic diseases including atherosclerosis, endothelial dysfunction, acute cardiac syndromes, cardiomyopathy, hypertrophy and heart failure, arrhythmias, hypertension, metabolic syndrome, obesity and fatty liver, diabetes mellitus, and dyslipidemia. The majority of these studies have been completed in animal models, but human studies are increasing. Preclinical studies were completed in either genetically manipulated mice (summarized in Table 1) or using STACs and NAD+ boosters to modulate sirtuin activity (summarized in Table 2).

随着年龄的增长,sirtuin 活性和 NAD + 水平的丧失与多种心血管和代谢疾病的发病机制有关,包括动脉粥样硬化、内皮功能障碍、急性心脏综合征、心肌病、肥厚和心力衰竭、心律失常、高血压、代谢症候群、肥胖和脂肪肝、糖尿病和血脂异常。这些研究大部分已经在动物模型中完成,但是人体研究正在增加。临床前研究在基因操纵的小鼠(见表1)中完成,或者使用 STACs 和 NAD + 助推器调节去乙酰化酶活性(见表2)。

Key Cardiac and Metabolic Effects 关键的心脏和代谢效应
Gain of Function 功能增益Loss of Function 功能丧失
SIRT1↑/↓ atherosclerosis 动脉粥样硬化↑/↓ atherosclerosis 动脉粥样硬化
↓ endothelial inflammation ↓内皮炎症↑ endothelial dysfunction, ↓ angiogenesis 内皮功能障碍,↓血管生成
↓ IR injury susceptibility 4. 红外线损伤敏感性↑ IR injury susceptibility 红外辐射易感性
↑/↓ hypertrophy and cardiomyopathy ↓肥大和心肌病↑/↓ hypertrophy ↓肥大
↓ hepatic steatosis 肝脏↓脂肪变性↑/↓ hepatic steatosis ↑肝脂肪变性
↓ obesity 4. ↓肥胖↑ obesity ↑型肥胖
↑/↔ glucose homeostasis ↑/something 葡萄糖稳态↑/↓ glucose homeostasis ↓葡萄糖稳态
↑/↓ serum lipid levels ↓血清脂质水平↑/↓ serum lipid levels ↓血清脂质水平
↓ hypertension 4. 高血压↑ arrhythmias 轻度心律失常
SIRT2↓ hypertrophy ↓肥大↑ hypertrophy and fibrosis 雌雄蕊肥大与纤维化
SIRT3↓ hypertrophy and fibrosis ↓肥大和纤维化↑ hypertrophy and fibrosis 雌雄蕊肥大与纤维化
↑ IR injury susceptibility 红外辐射易感性
↑ obesity ↑型肥胖
↑/↔ insulin resistance 胰岛素抵抗
↑ serum lipid levels 血清脂蛋白
SIRT4↑ hypertrophy and cardiac dysfunction 脑肥大与心功能障碍↓ hypertrophy and fibrosis ↓肥大和纤维化
↓ obesity 4. ↓肥胖
↑ insulin resistance 胰岛素抵抗
SIRT5↑ IR injury susceptibility 红外辐射易感性
↑ hypertrophy and fibrosis 雌雄蕊肥大与纤维化
SIRT6↓ hypertrophy ↓肥大↑ hypertrophy 雌雄成熟
↓ obesity 4. ↓肥胖↑ obesity ↑型肥胖
↑ glucose homeostasis, ↑ insulin sensitivity 葡萄糖↑稳态,胰岛素敏感性↓ glucose homeostasis 4. 葡萄糖的内稳态
↓ serum lipid levels 4. 血清脂质水平↑ serum lipid levels 血清脂蛋白
SIRT7↑ hypertrophy and fibrosis 雌雄蕊肥大与纤维化
↓ systolic function 心脏收缩功能↓
↓ hepatic steatosis 肝脏↓脂肪变性
↓ glucose intolerance 名片↓葡萄糖耐受不良

IR indicates ischemia-reperfusion; and SIRT, sirtuin.

IR 表明缺血再灌注; SIRT,sirtuin。

IR indicates ischemia-reperfusion; and SIRT, sirtuin.

IR 表明缺血再灌注; SIRT,sirtuin。

Drug 药物Disease 疾病Model 模型Effects 效果References参考资料
NR 天然橡胶Metabolic syndrome 代谢症候群HFD in mice 小鼠手足口病↓ fat mass ↑ insulin sensitivity ↓ LDL 的胰岛素敏感度↓59
NMN 核磁共振成像Endothelial dysfunction 内皮功能障碍Aging mice 衰老的老鼠↑ capillary density ↑ endothelial function 血管内皮功能60
Aging mice 衰老的老鼠↑ capillary density ↑ endurance ↑毛细管密度61
Hypertrophy 肥大Cardiomyopathy mouse 心肌病小鼠↑ cardiac function ↑心功能62
TAC in mice 老鼠体内的 TAC↓ hypertrophy ↓肥大63
Cardiomyopathy 心肌病Ndufs4 KO mice 4 KO 鼠↓ sensitivity to pressure overload 4. 对压力过载的敏感64
IR injury 红外损伤Ischemia in mice 小鼠局部缺血↓ ischemic damage ↓缺血性损伤65
NR 天然橡胶Cardiomyopathy 心肌病Aged MDX mice 衰老的 MDX 鼠↓ inflammation and fibrosis 4. 名片↓炎症和纤维化66
Resveratrol 白藜芦醇Hypertrophy 肥大Rats+doxorubicin 大鼠 + 阿霉素↓ fibrosis ↓ diastolic dysfunction ↓纤维性舒张功能障碍67
TAC in rats 老鼠体内的 TAC↑ cardiac function ↑心功能68
Dahl salt-sensitive rats 对盐敏感的老鼠↑ cardiac function ↓ hypertrophy ↑心脏功能肥大69
Spontaneously hypertensive rats 自发性高血压大鼠↑ cardiac function ↓ hypertrophy ↑心脏功能肥大70
TAC in mice 老鼠体内的 TAC↑ cardiac function ↓ hypertrophy ↑心脏功能肥大36
Cardiomyopathy 心肌病TO-2 hamster TO-2仓鼠↓ fibrosis ↑ cardiac function ↓心肌纤维化71
Type 1 diabetes mellitus model 1型糖尿病模型↑ cardiac function ↑心功能72
Autoimmune myocarditis 自身免疫性心肌炎↑ cardiac function ↓ hypertrophy ↓ fibrosis ↓肥大的心脏纤维化73
Endothelial dysfunction 内皮功能障碍Rats+cigarette smoke 老鼠 + 香烟烟雾↓ ROS ↑ vascular relaxation ↓ ROS ↑血管松弛74
Rhesus monkeys+HFD 恒河猴 + 手足口病↓ arterial stiffening ↓ inflammation ↓硬化的动脉炎症75
Rat MI model 大鼠心肌梗死模型↑ angiogenesis ↑ cardiac function 血管生成↑心功能76
I/R injury I/R 损伤IR in mice 老鼠的红外线↓ ischemic damage ↓缺血性损伤77
IR in rats 大鼠红外线↓ ischemic damage ↓缺血性损伤78
Insulin/glucose regulation 胰岛素/葡萄糖调节Rhesus monkeys+HFD 恒河猴 + 手足口病↑ insulin sensitivity 胰岛素↑敏感性79
Mice+HFD 鼠标 + 手足口病↑ lifespan ↑ insulin sensitivity 寿命↑胰岛素敏感性80
Mice+HFD 鼠标 + 手足口病↓ obesity ↑ insulin sensitivity 胰岛素敏感性81
SRT2104Insulin/glucose regulation 胰岛素/葡萄糖调节Mice 老鼠↑ lifespan ↑ insulin sensitivity 寿命↑胰岛素敏感性17
SRT1720Metabolic syndrome 代谢症候群Mice 老鼠↑ lifespan ↓ metabolic syndrome ↓ cholesterol ↓代谢症候群胆固醇16
Genetically obese mice 遗传性肥胖老鼠↑ lifespan ↓ serum glucose ↑血清葡萄糖32
Mice+HFD 鼠标 + 手足口病↓ obesity ↑ endurance ↓ insulin resistance ↓肥胖↑耐力↓胰岛素抵抗82
Mice+HFD 鼠标 + 手足口病↑ lifespan ↓ insulin resistance ↓ hepatic steatosis 胰岛素抵抗↓肝脂肪变性83
Endothelial dysfunction 内皮功能障碍Aging mice 衰老的老鼠↑ vascular relaxation ↓ superoxide ↓ inflammation ↓过氧化物的炎症84
SRT3025Astherosclerosis 动脉粥样硬化ApoE KO+HFD 载脂蛋白 e ko + 手足口病↓ serum LDL and cholesterol ↓ astherosclerosis 4. 名片↓血清低密度脂蛋白和胆固醇硬化85
Curcumin 姜黄素IR injury 红外线损伤IR in rats+curcumin 大鼠红外光谱 + 姜黄素↑ cardiac function ↓ ischemic damage ↑心脏功能缺血性损害86
Honokiol 女名女子名Hypertrophy 肥大TAC in mice 老鼠体内的 TAC↓ hypertrophy ↓ fibrosis 4. ↓肥大的纤维化40
Mice+doxorubicin 小鼠 + 阿霉素↓ oxidative stress 名片↓氧化应激41
4-aminobenzamide 4- 氨基苯甲酰胺Endothelial dysfunction 内皮功能障碍Diabetes mellitus rat model 糖尿病大鼠模型↓ endothelial dysfunction ↓ inflammation ↓内皮功能障碍炎症87
Luteolinidin 木犀草素IR injury 红外线损伤Isolated rat hearts 分离的老鼠心脏↓ endothelial dysfunction ↓ contractile dysfunction ↓内皮功能障碍↓收缩功能障碍88
Apigenin 芹菜素Metabolic syndrome 代谢症候群Mice+HFD 鼠标 + 手足口病↓ glucose dysregulation 4. 葡萄糖↓调节失调53

ApoE indicates apolipoprotein E; HFD, high-fat diet; I/R; ischemia/reperfusion; KO, knockout; LDL, low-density lipoprotein; MI, myocardial infarction; NAD+, nicotinamide adenine dinucleotide; NMN, nicotinamide mononucleotide; NR, nicotinamide riboside; ROS, reactive oxidative species; STAC, sirtuin-activating compound; and TAC, transverse aortic constriction.

载脂蛋白 e 表明 E型载脂蛋白质; 高脂饮食; I/R; 缺血/再灌注; KO,敲除; 低密度脂蛋白,低密度脂蛋白; 心肌梗死,心肌梗死; NAD + ,烟酰胺腺嘌呤二核苷酸; NMN,烟酰胺单核苷酸; NR,烟酰胺核糖苷; ROS,活性氧化物; STAC,sirtuin-activating 化合物; TAC,横向主动脉收缩。

Atherosclerosis

动脉粥样硬化

Atherosclerosis is the major risk factor for myocardial infarction, coronary artery disease, and stroke in the older population. It is the number one cause of death in the developed world, and the incidence of atherosclerosis increases with age.89 Atherosclerosis results from increased LDL (low-density lipoprotein) cholesterol in the plasma, dysfunctional endothelial cells, endothelial oxidative stress, an inflammatory response, and ultimately plaque formation90,91 (Figure 2). Risk factors for atherosclerosis, along with age, include hypercholesterolemia, metabolic syndrome, hypertension, obesity, and type 2 diabetes mellitus.89 Sirtuins and NAD+ play a role in the modulation of many of these risk factors, and there is increasing evidence that sirtuins may also modulate atherosclerosis itself (Figure 2). SIRT1 levels are decreased in atherosclerotic regions of patients.92,93 Monocytes isolated from patients with coronary artery disease also have lower SIRT1 levels than control patients,94 suggesting a systemic decrease in SIRT1 in this disease.


在老年人群中,动脉粥样硬化是心肌梗死、冠状动脉疾病和中风的主要危险因素。动脉粥样硬化是由于血浆中低密度脂蛋白(低密度脂蛋白)胆固醇升高,内皮功能障碍,内皮细胞氧化应激,炎症反应,最终形成血小板90,91(图2)。随着年龄的增长,动脉粥样硬化的危险因素包括高胆固醇血症、代谢症候群、高血压、肥胖和2型糖尿病。在患者的动脉粥样硬化区域 SIRT1水平降低,92,93单核细胞分离自冠状动脉疾病的患者也比对照组患者有较低的 SIRT1水平,94表明在这种疾病的 SIRT1系统性减少。

Figure 2.
Figure 2. The role of sirtuins and nicotinamide adenine dinucleotide (NAD+) in the aging vasculatureA, A young blood vessel shows healthy vascular smooth muscle cells (VSMCs), lined with healthy endothelial cells. Stimulation with nitric oxide (NO) results in vessel contraction. Angiogenesis, the growth of new blood vessels, is induced when vascular endothelial growth factor (VEGF) acts on SIRT1 to relieve notch intracellular domain (NICD) inhibition of Notch. B, Aging results in changes to the structure and function of the vasculature. With increasing age, there are increased atherosclerotic plaques, increased low-density lipoprotein (LDL) cholesterol in the blood stream, decreased sprouting angiogenesis, increased thrombosis, increased oxidative stress, decreased nitric oxide, increased inflammation, senescence of endothelial cells and VSMCs, arterial thickening, and fibrosis. These changes contribute to reduced blood flow and reduced reactivity of the blood vessels in aging. Sirtuins and NAD+ can improve or reverse some aspects of vascular aging (marked in blue on the figure) through modulation of targets (marked in brown). In particular, SIRT1 decreases LDL cholesterol levels, reduces vascular cell senescence, increases NO through endothelial nitric oxide synthase (eNOS), reduces inflammation through nuclear factor κ-light-chain-enhancer of activated B cells (NFκB) modulation, decreases oxidative stress by modulating forkhead box (FOXOs) and thrombosis via tissue factor (TF) and peroxisome proliferator-activated receptor delta (PPARδ), and increases angiogenesis through modulation of FOXO1 and NICD-Notch. SIRT3 also has a protective role in angiogenesis, and NAD+ reduces vascular inflammation. Figure made using adapted images from http://smart.servier.com.图2。去乙酰化酶和烟酰胺腺嘌呤二核苷酸在衰老脉管系统中的作用。年轻的血管显示健康的血管平滑肌细胞,内衬健康的内皮细胞。一氧化氮(NO)刺激导致血管收缩。血管生成是指血管内皮生长因子(VEGF)作用于 SIRT1,减轻 Notch 缺口细胞内结构域(NICD)的抑制,从而诱导新生血管的形成。老化导致血管结构和功能的改变。随着年龄的增长,动脉粥样硬化斑块增多,血流中低密度脂蛋白(LDL)胆固醇升高,血管生成减少,血栓形成增加,氧化应激增加,一氧化氮减少,炎症增加,内皮细胞和 VSMCs 衰老,动脉增厚,纤维化。这些变化有助于减少血流量和血管的反应性在老化。去乙酰化酶和 NAD + 可以通过调节靶蛋白(棕色标记)改善或逆转血管老化的某些方面(图中蓝色标记)。特别是,SIRT1降低低密度脂蛋白胆固醇水平,减少血管细胞衰老,通过内皮一氧化氮合酶增加一氧化氮,通过核因子轻链增强剂活化的 b 细胞(nf b)调节减少炎症,通过调节 FOXOs 和组织因子(TF)和过氧化物酶体增殖物活化受体增殖因子(ppar)降低氧化应激,通过调节 FOXO1和 NICD-Notch 增加血管生成。SIRT3在血管新生方面也有保护作用,NAD + 可以减少血管炎症。这张图片是根据 http://smart.servier.com 图片改编而成的。

Preclinical studies have shown a protective role for SIRT1 in atherosclerosis, at least in vascular endothelial and smooth muscle cells. Apolipoprotein E (ApoE) knockout mice have increased serum cholesterol levels and can be used as a model of atherosclerosis, especially when fed a high-fat diet (HFD). ApoE knockout mice have reduced SIRT1 expression,95 particularly in atherosclerotic plaques.93 Endothelial cell–specific overexpression of SIRT1 in ApoE knockout mice protects against atherosclerotic plaques.96 In addition, ApoE knockout mice crossed with smooth muscle cell–specific SIRT1 knockout mice showed increased atherosclerosis.93 Treatment of ApoE knockout mice with the STAC SRT3025 reduced atherosclerosis in these mice by increasing LDL uptake.85 However, whole-body SIRT1 overexpressors that were placed on an atherogenic diet to induce plaque formation had worse lipid profiles and more severe atherosclerosis than wild-type mice on the same diet.97 The proposed mechanism was increased lipid accumulation and secretion in the liver as a result of Creb modulation which resulted in overall proatherogenic effects despite potential benefits of SIRT1 overexpression in the vasculature.97 More research is needed to understand the complex role of SIRT1 in lipid metabolism in the liver, especially in the context of HFD or high-cholesterol diet. This is discussed further in sections Diabetes, Glucose/Insulin Dysregulation and Metabolic Syndrome and Dyslipidemia.

临床前研究表明,SIRT1在动脉粥样硬化中具有保护作用,至少在血管内皮细胞和平滑肌细胞中是如此。E型载脂蛋白质基因敲除小鼠血清胆固醇水平升高,可以用作动脉粥样硬化的模型,特别是喂食高脂肪饮食的小鼠。载脂蛋白 e 基因敲除小鼠减少了 SIRT1的表达,尤其是在动脉粥样硬化斑块中的表达。93载脂蛋白 e 基因敲除小鼠内皮细胞特异性 SIRT1过表达对动脉粥样硬化斑块的保护作用。96此外,载脂蛋白 e 基因敲除小鼠与平滑肌细胞特异性 SIRT1基因敲除小鼠杂交,显示动脉粥样硬化增加。93 STAC SRT3025对载脂蛋白 e 基因敲除小鼠的治疗通过增加低密度脂蛋白的摄取来减少这些小鼠的动脉粥样硬化。85然而,与同样饮食的野生型小鼠相比,在致动脉粥样硬化饮食中诱导斑块形成的全身 SIRT1过量表达者的血脂状况更差,动脉粥样硬化更严重。97提出的机制是由于 Creb 的调节导致肝脏脂质的积累和分泌增加,尽管 SIRT1在血管中过度表达可能有益,但仍然导致了整体的促动脉粥样硬化效应。97还需要更多的研究来了解 SIRT1在肝脏中脂质代谢的复杂作用,特别是在高胆固醇饮食或高胆固醇饮食的情况下。这在糖尿病、血糖/胰岛素调节失调、代谢症候群和血脂异常等章节中进一步讨论。

Other factors associated with atherosclerosis are also modulated by SIRT1. Age-related dedifferentiation of vascular smooth muscle cells is implicated in the disease, and the induction of SIRT1 with resveratrol can promote differentiation of these cells and may contribute to protection against atherosclerosis.98 Thrombosis contributes to an increased risk of ruptured plaques and clots in atherosclerosis. In mice, inhibition of SIRT1 with sirtinol results in increased tissue factor expression and thrombi promotion, indicating SIRT1 may protect against thrombosis.99,100 Interestingly, treatment with resveratrol to increase sirtuin activity reversed the prothrombotic status of cyclooxygenase-2 knockout mice.99

其他与动脉粥样硬化相关的因素也受到 SIRT1的调控。与年龄相关的血管平滑肌细胞脱分化与这种疾病有关,白藜芦醇诱导 SIRT1可以促进这些细胞的分化,可能有助于防止动脉粥样硬化。在小鼠中,SIRT1与 sirtinol 抑制结果增加组织因子表达和促进血栓,表明 SIRT1可能保护对血栓形成。有趣的是,白藜芦醇增加 sirtuin 活性治疗扭转了环氧合酶 -2基因敲除小鼠的血栓形成状态

Overall, the majority of studies show a protective role of SIRT1 in modulating atherosclerosis and many of the factors that contribute to its development. Increasing SIRT1 activity should be further investigated as a promising treatment option for atherosclerosis and its risk factors. More research is needed, however, to confirm the role of SIRT1 in lipid modulation in the liver in the context of different diets and the effect of this on atherosclerosis.

总的来说,大多数研究表明 SIRT1在调节动脉粥样硬化和许多有助于其发展的因素中具有保护作用。增加 SIRT1活性应该作为动脉粥样硬化及其危险因素的一个有前途的治疗选择进一步研究。然而,还需要更多的研究来证实 SIRT1在不同饮食背景下肝脏脂质调节中的作用以及它对动脉粥样硬化的影响。

There are limited studies exploring the effect of the other sirtuins and NAD+ in atherosclerosis. Knockout of SIRT3 in mice lacking the LDL receptor had no effect101 while SIRT6 gene variants have been associated with the development of plaques in patients.102 Inhibition of NAMPT with the drug FK866 in ApoE knockout mice resulted in reduced C-X-C motif chemokine 1 (CXCL1) chemokine levels and thus reduced neutrophil infiltration in atherosclerotic plaques,103indicating a potential role of NAD+ in increasing inflammation in atherosclerosis.

关于其他去乙酰化酶和 NAD + 在动脉粥样硬化中的作用的研究很少。102抑制药物 FK866在 ApoE 基因敲除小鼠中导致 CXCL1水平降低,从而减少动脉粥样硬化斑块中中性粒细胞的浸润,103表明 NAD + 在动脉粥样硬化炎症增加中的潜在作用。

Endothelial Dysfunction and Artery Stiffness

内皮功能障碍与动脉僵硬

A hallmark of vascular aging is increased dysfunction of the vascular endothelium, characterized by a reduced nitric oxide (NO)–mediated vasodilatory response to stimuli. In addition, with aging, there are changes to the vascular smooth muscle cells, which result in increased arterial stiffness and reduced elasticity.104,105 These changes reduce the ability of the vasculature to relax and dilate in old age and are associated with an increased risk of a range of cardiovascular diseases, including hypertension, heart failure, and coronary artery disease.104 The role of SIRT1 has been explored in the context of endothelial dysfunction and seems to contribute to normal endothelial activity and protect against dysfunction in aging and other models of damage (Figure 2).

血管老化的一个标志是增加血管内皮功能障碍,拥有属性一氧化氮(NO)介导的血管扩张反应减少刺激。此外,随着年龄的增长,血管平滑肌细胞也发生了变化,导致动脉硬度增加和弹性降低。这些变化降低了血管系统在老年时放松和扩张的能力,并与一系列心血管疾病的风险增加有关,包括高血压、心力衰竭和冠状动脉疾病。

Inhibition of SIRT1 is associated with poor vascular function and increased artery stiffness. Mice with knockout of both ApoE and SIRT1 show increased endothelial superoxide production and increased NFκB compared with the ApoE knockout alone, indicating a role of SIRT1 in reducing endothelial dysfunction, at least in the context of atherosclerosis.106 SIRT1 inhibition with sirtinol in young wild-type mice resulted in artery stiffness to a similar level to that seen in aging wild-type mice.107 Specific inhibition of SIRT1 in the arterial endothelium of mice resulted in a reduction in NO and an inhibition of endothelium-dependent vasodilation.108 Importantly, the same study showed in vitro that SIRT1 increased endothelial NO by directly deacetylating and thus stimulating the activity of endothelial NO synthase.108

SIRT1的抑制与血管功能不良和动脉僵硬度增加有关。与单独使用载脂蛋白 e 基因敲除的小鼠相比,同时敲除载脂蛋白 e 和 SIRT1的小鼠表现出内皮超氧化物产生增加和 nf b 增加,这表明 SIRT1在减少内皮功能障碍方面的作用,至少在动脉粥样硬化的情况下。106 SIRT1抑制 sirtinol 在年轻的野生型小鼠导致动脉僵硬度相似的水平,看到老龄野生型小鼠。107 SIRT1在小鼠动脉内皮细胞中的特异性抑制作用导致 NO 的减少和内皮依赖性血管舒张功能的抑制。108重要的是,同样的研究显示 SIRT1通过直接去乙酰化增加内皮 NO 合成酶的活性,从而刺激内皮 NO 合成酶的活性。108

Several studies have explored the protective effects of increasing SIRT1 activity on the vascular endothelium. A cigarette smoke model of vascular aging in rats resulted in impaired artery relaxation, increased reactive oxidative species, and increased inflammatory markers. Activation of SIRT1 either genetically or with resveratrol prevented these effects on the vasculature.74 SIRT1-overexpressing mice fed an HFD had better endothelium-dependent vasorelaxation, and increased endothelial NO synthase expression, compared with wild-type mice fed an HFD.96 SIRT1 activation with SRT1720 in old mice restored endothelial function by increasing cyclooxygenase-2–mediated dilation and also reduced superoxide production and decreased inflammation.84 SIRT1 also acts to prevent senescence of endothelial cells, which may contribute to vascular endothelial dysfunction in aging.109,110 Importantly for clinical translation in rhesus monkeys, increasing SIRT1 activity with resveratrol treatment prevented arterial stiffening and inflammation,75 and a human study found that in older patients with stiffer vessels there was reduced SIRT1 expression in artery endothelial cells.107

多项研究探讨了提高 SIRT1活性对血管内皮细胞的保护作用。香烟烟雾造成大鼠血管老化,导致损害动脉松弛,增加反应性氧化物种,增加炎症标记物。SIRT1基因的激活或白藜芦醇的激活可以阻止这些对血管系统的影响。与喂食 HFD 的野生型小鼠相比,74只 sirt1高表达的 HFD 小鼠具有更好的内皮依赖性血管舒张功能,内皮一氧化氮合酶表达增加。96 SIRT1激活 SRT1720可通过增加环氧合酶 -2介导的舒张功能恢复内皮功能,并降低超氧化物产生和炎症反应。84 SIRT1还具有延缓内皮细胞衰老的作用,这可能与老化过程中血管内皮功能障碍有关。109,110在恒河猴的临床研究中很重要的一点是,白藜芦醇治疗增加 SIRT1的活性可以防止动脉硬化和炎症,一项人类研究发现,在血管更硬的老年患者中,动脉内皮细胞中 SIRT1的表达减少。107

The role of the other sirtuins in endothelial dysfunction has not been well characterized. SIRT6 seems to have a role in protecting against endothelial cell senescence,111,112 which may contribute to protection against age-related endothelial dysfunction. NAD+ may also have a protective role in the aging vasculature as NMN treatment of old mice improved endothelial relaxation in arteries and reduced artery stiffness.60 Treatment with a PARP1 inhibitor in a diabetes mellitus–induced vascular dysfunction rat model was shown to prevent endothelial dysfunction and inflammation although NAD+levels were not explicitly investigated.87 Targeting detrimental changes to the endothelium in aging with SIRT1 activators or NAD+ boosters shows promise as an area of focus for treating age-related vascular dysfunction and arterial stiffening.

其他去乙酰化酶在内皮功能障碍中的作用还没有得到很好的描述。SIRT6似乎有保护内皮细胞衰老的作用,111,112这可能有助于防止与年龄有关的内皮功能障碍。用 PARP1抑制剂治疗糖尿病诱导的血管功能障碍大鼠模型被证明可以预防内皮功能障碍和炎症,尽管 NAD + 水平没有被明确研究。

Angiogenesis

血管生成

Angiogenesis, which involves endothelial cell proliferation and migration in response to vascular endothelial growth factor, is also decreased in aging.113 Angiogenesis may have a protective role in cardiovascular disease by increasing blood flow and myocardial function, especially in ischemic heart disease.114,115

血管新生可能通过增加血流量和心肌功能在心血管疾病中发挥保护作用,尤其是在血管内皮生长因子冠状动脉疾病

SIRT1 and SIRT3 have both been shown to have roles in inducing angiogenesis. SIRT1 acts as a negative regulator of Notch and FOXO1, key regulators of blood vessel growth.116 In vitro studies show that SIRT1 knockout results in reduced angiogenesis of endothelial cells.117 In mice and zebrafish, a reduction in SIRT1 reduces sprouting blood vessel formation.117 A more recent study showed that in aged endothelial cell–specific SIRT1 knockout mice, there is reduced capillary density which was exacerbated by transverse aortic constriction (TAC), an intervention to model hypertrophy, and heart failure in mice.118 In vitro studies showed that SIRT1 knockout resulted in reduced angiogenic response to vascular endothelial growth factor, possibly because of reduced expression of the vascular endothelial growth factor receptors FLT1 (Fms-related tyrosine kinase 1) and FLK2 (fetal liver kinase-2).118 Resveratrol pretreatment to increase SIRT1 activity in a rat myocardial infarction model upregulated modulators of angiogenesis and increased capillary density which ultimately resulted in improved cardiac function.76 Bone marrow cell treatment increased angiogenesis and improved cardiac function in a mouse model of myocardial infarction.119 Interestingly, it seems that SIRT3 is required for this protection as treatment with bone marrow cells isolated from SIRT3 knockout mice did not result in angiogenesis or the associated cardiac benefits.119

SIRT1和 SIRT3都被证明在诱导血管生成方面有作用。SIRT1是 Notch 和 FOXO1的负调节因子,FOXO1是血管生长的关键调节因子。116体外研究表明 SIRT1基因敲除导致内皮细胞血管生成减少。117在小鼠和斑马鱼中,SIRT1的减少减少了出芽血管的形成。117最近的一项研究表明,在老年内皮细胞特异性 SIRT1基因敲除小鼠中,毛细血管密度降低,并且由于横向主动脉收缩(TAC) ,一种对心肌肥大和心力衰竭的干预而加剧。118. 体外研究表明,SIRT1基因敲除导致对血管内皮生长因子的血管生成反应减少,可能是因为血管内皮生长因子受体 FLT1(fms 相关的酪氨酸激酶1)和 FLK2(胎儿肝激酶2)的表达减少。118白藜芦醇预处理增加 SIRT1活性在大鼠心肌梗死模型上调血管生成的调节剂和增加毛细血管密度,最终导致改善心脏功能。76骨髓细胞治疗增加了心肌梗死模型小鼠的血管生成和改善心脏功能。119有趣的是,SIRT3似乎需要这种保护作用,因为从 SIRT3基因敲除小鼠中分离的骨髓细胞治疗并没有导致血管生成或相关的心脏益处。119

In addition, recent findings showed that NMN treatment in aging mice resulted in a reversal of the age-related decline in capillary density and blood flow in muscles, which resulted in increased mobility and endurance.61 Importantly, the authors demonstrated that the mechanism of reduced blood flow with aging is related to reduced NAD+-dependent SIRT1 activity and that increasing the NAD+-SIRT1 axis with NMN resulted in SIRT1-dependent inhibition of Notch1 intracellular domain and promoted vascular endothelial growth factor–stimulated sprouting angiogenesis61 (Figure 3). Hydrogen sulfide was also shown to improve angiogenesis via NAD+– and SIRT1-dependent mechanisms61 although the exact mechanism of the hydrogen sulfide-SIRT1 interaction remains to be elucidated.120 Furthermore, Das et al61found that NMN treatment also increased sprouting of aortic rings from aging wild-type, but not SIRT1 knockout mice, indicating that NMN may also be beneficial in inducing SIRT1-dependent angiogenesis in tissues other than skeletal muscle.

此外,最近的研究结果表明,NMN 治疗老龄小鼠导致逆转年龄相关的毛细血管密度和肌肉血流量下降,从而导致运动和耐力的增加。61重要的是,作者证明血流量随着年龄增长而减少的机制与降低 NAD + 依赖的 SIRT1活性有关,增加 NAD +-SIRT1轴与 NMN 细胞内 nrt1结构域导致 SIRT1依赖性抑制和促进血管内皮生长因子刺激的血管发芽基因61(图3)。此外,Das 等人还发现,NMN 治疗也增加了老化野生型小鼠主动脉环的萌芽,但不增加 SIRT1基因敲除小鼠的萌芽,这表明 NMN 也可能有利于诱导 SIRT1基因敲除小鼠骨骼肌以外的组织中的血管生成。

Figure 3.
Figure 3. The role of SIRT1 and nicotinamide adenine dinucleotide (NAD+) in age-related endothelial dysfunction. In young healthy capillaries, angiogenesis occurs after stimulation of endothelial cells with vascular endothelial growth factor (VEGF) released from myocytes. Characteristic changes of the vasculature with old age include dysfunctional endothelial cells and reduced VEGF-induced angiogenesis. These age-related changes result in reduced capillary density, reduced blood flow, and ultimately reduced mobility and endurance. A mechanism of this reduced angiogenesis in old age is reduced endothelial SIRT1 and NAD+, which ostensibly reduces the sensitivity of endothelial cells to VEGF. Increasing the hydrogen sulfide (H2S)-NAD+-SIRT1 axis in endothelial cells, either with NaHS to boost H2S, NMN to boost NAD+, or with exercise, causes SIRT1-dependent inhibition of Notch intracellular domain (NICD), which results in increased sprouting angiogenesis. These interventions can reverse endothelial dysfunction and increase angiogenesis in old age to return capillary density and endurance to the levels of that seen in young mice. Figure derived from Das et al61 using adapted images from http://smart.servier.com.图3。SIRT1和烟酰胺腺嘌呤二核苷酸在老年相关性内皮功能障碍中的作用。在年轻健康的毛细血管中,刺激内皮细胞后,心肌细胞释放出血管内皮生长因子(VEGF) ,促进血管生成。老年血管的特征性改变包括内皮细胞功能障碍和血管内皮生长因子诱导的血管生成减少。这些与年龄有关的变化导致毛细血管密度降低,血流量减少,最终降低流动性和耐力。老年期血管生成减少的一个机制是内皮细胞 SIRT1和 NAD + 的减少,这表面上降低了内皮细胞对 VEGF 的敏感性。增加内皮细胞中的硫化氢(H2S)-NAD +-SIRT1轴,不论是用 NaHS 增加 H2S,NMN 增加 NAD + ,还是用运动,都可以引起内皮细胞内 Notch 结构域(NICD)的 SIRT1依赖性抑制,从而导致血管生成增加。这些干预可以逆转内皮功能障碍,增加老年血管生成,使毛细血管密度和耐受力恢复到年轻小鼠的水平。图源自 Das et al61,使用的图片改编自 http://smart.servier.com。

These promising results indicate that NAD+ boosters and sirtuin activators can be used to increase angiogenesis in cardiovascular diseases and age-related blood flow dysfunction.

这些有希望的结果表明 NAD + 助推剂和去乙酰化酶激活剂可用于增加心血管疾病的血管生成和年龄相关的血流功能障碍。

Ischemia-Reperfusion Injury

缺血再灌注损伤

Many studies over the past decade have investigated the role of sirtuins and NAD+ in the context of ischemia-reperfusion (IR) injury. IR injury occurs clinically in the context of myocardial infarction or during cardiovascular surgery when blood supply to the heart, or part of the heart, is stopped. The period of ischemia can result in tissue injury and cell death as a result of rapidly reduced ATP levels. This damage is exacerbated by rapid reperfusion, which results in the induction of oxidative stress and apoptosis. IR injury increases with age,121 and periods of ischemia or hypoxia in cardiomyocytes are associated with a reduction in endogenous NAMPT,65,122 as well as downregulation of SIRT1,123SIRT3,124 and SIRT4.125

在过去的十年中,许多研究已经探讨了去乙酰化酶和 NAD + 在缺血再灌注(IR)损伤中的作用。胰岛素抵抗损伤发生在临床心肌梗死或心血管手术中,当心脏或部分心脏的血液供应停止时。缺血时期会导致组织损伤和细胞死亡,因为 ATP 水平迅速降低。快速再灌注加重了这种损伤,导致氧化应激和细胞凋亡的诱导。IR 损伤随年龄、心肌细胞缺血或缺氧时间的延长而增加,与内源性 NAMPT、65、122、 SIRT1、123 SIRT3、124和 SIRT4.125下调有关

Increasing SIRT1 has a protective role in IR injury (Figure 4). Cardiac-specific SIRT1 knockout mice display increased cardiac damage after exposure to IR while mice overexpressing SIRT1 in the heart are protected from IR damage.123Overexpression of SIRT1 resulted in upregulation of antioxidant pathways mediated by FOXO1 and manganese superoxide dismutase and downregulation of proapoptotic pathways mediated by caspase 3 and Bax.123 A similar role of SIRT1 was observed in rats exposed to IR injury,86 and resveratrol pretreatment protected both mice and rats from IR injury.77,78 Other in vitro studies have shown the same antiapoptotic role of SIRT1 by mediating FOXO1 expression, in the context of hypoxia.126

增加 SIRT1在 IR 损伤中具有保护作用(图4)。SIRT1的过度表达导致 FOXO1和锰超氧化物歧化酶介导的抗氧化通路的上调,以及 caspase3和 Bax 介导的促凋亡通路的下调。 SIRT1的类似作用在 IR 损伤的大鼠中观察到,86和白藜芦醇预处理保护小鼠和大鼠免受 IR 损伤。77,78其他体外研究表明 SIRT1在缺氧环境中通过介导 FOXO1的表达具有同样的抗凋亡作用

Figure 4.
Figure 4. The role of sirtuins and nicotinamide adenine dinucleotide (NAD+) in age-related metabolic and heart diseases. In old age, there is increased risk of cardiovascular and metabolic diseases, including fatty liver, dyslipidemia, obesity, type 2 diabetes mellitus, hypertension, arrhythmias, fibrosis, hypertrophy, and ischemia/reperfusion injury. Sirtuins and NAD+ have roles in protecting against or preventing the development of these diseases (shown in blue on figure) through modulation of a variety of proteins (shown in brown on figure). SIRT1, 3, 6 and NAD+ have roles in modulating dyslipidemia, with the liver X receptor (LXR) and malonyl-CoA decarboxylase (MCD) identified as targets, and SIRT1, 3, 4, and 6 have roles in preventing obesity. SIRT1, 3, 4, 6, 7 and NAD+ may have protective roles in type 2 diabetes mellitus and identified targets include mitochondrial uncoupling protein 2 (UCP2), peroxisome proliferator-activated receptor γ coactivator 1-α (PGC1α), and forkhead box 1 (FOXO1). SIRT1 and 3 have protective roles in hypertension, and SIRT1, 2, 3, 5, 7 and NAD+ have been associated with reduced cardiac fibrosis. SIRT1, 2, 3, 4, 6, 7 and NAD+ protect against cardiac hypertrophy with identified targets, including the mitochondrial permeability transition pore (mPTP), insulin-like growth factor (IGF)-1, peroxisome proliferator-activated receptor α (PPARα), eukaryotic initiation factor 2 (elF2a), FOXO3a, and AMP-activated protein kinase (AMPK). SIRT1, 3, 5 and NAD+ protect against ischemia/reperfusion injury via FOXO1, manganese superoxide dismutase (MnSOD), B-cell lymphoma 2 (Bcl-2)–associated X protein (Bax), and succinate dehydrogenase (SDH). SIRT1, 2 and NAD+ improve arrhythmias via sodium channel Nav1.5 and BubR1. Figure made using adapted images from http://smart.servier.com.

图4。去乙酰化酶和烟酰胺腺嘌呤二核苷酸在与年龄相关的代谢和心脏疾病中的作用。老年人患心血管和代谢疾病的风险增加,包括脂肪肝、血脂异常、肥胖、2型糖尿病、高血压、心律失常、纤维化、肥大和缺血/再灌注损伤。Sirtuins 和 NAD + 通过调节各种蛋白质(图中棕色部分) ,在防止或预防这些疾病的发展中起作用(图中蓝色部分)。SIRT1,3,6和 NAD + 在调节血脂异常方面有作用,以肝X受体和丙二酰辅酶A脱羧酶为目标,SIRT1,3,4和6在预防肥胖方面有作用。SIRT1、3、4、6、7和 NAD + 可能在2型糖尿病中起保护作用,已确定的靶点包括线粒体解偶联蛋白2(UCP2)、过氧化物酶体增殖物活化受体辅激活子1- (pgc1)和叉头盒1(FOXO1)。SIRT1和3在高血压中具有保护作用,SIRT1、2、3、5、7和 NAD + 与减少心肌纤维化有关。SIRT1,2,3,4,6,7和 NAD + 对心肌肥大具有保护作用,其靶点包括线粒体通透性转换孔(mPTP)、胰岛素样生长因子(IGF)-1、过氧化物酶体增殖物活化受体(ppar)、真核起始因子2(elF2a)、 FOXO3a 和 AMP活化蛋白激酶(AMPK)。SIRT1,3,5和 NAD + 通过 FOXO1,MnSOD,b 细胞淋巴瘤2(Bcl-2)相关 x 蛋白(Bax)和超氧化物歧化酶琥珀酸脱氢酶(SDH)对缺血/再灌注损伤的保护作用。SIRT1、2和 NAD + 通过钠通道 Nav1.5和 BubR1改善心律失常。这张图片是根据 http://smart.servier.com 图片改编而成的。

The mitochondrial sirtuins SIRT3, 4, and 5 also have protective roles in IR injury. In vitro studies of SIRT3 overexpression in cardiomyocytes exposed to hypoxia showed protection against cell damage via a downregulation of apoptosis involving Ku70 and Bax.127 The same role is seen in vivo, where SIRT3 knockout mice are more susceptible to IR injury and have increased damage and reduced mitochondrial function postinjury when compared with wild-type mice.121 Overexpression of SIRT4 in cardiomyoblast cells increased their viability posthypoxia by decreasing caspase activity and apoptosis, while knockdown of SIRT4 in the same cells results in reduced viability and an induction of apoptosis.125 SIRT5 knockout mice have increased infarct size after IR injury compared with wild-type mice and an inhibitor of succinate dehydrogenase protected against this injury, implying a role of SIRT5 in modulating protein succinylation in the heart in the context of IR injury.128 In vitro studies also support a role of SIRT5 in protecting against IR injury, at least in part by reducing apoptosis.129

线粒体 sirtuins SIRT3、4和5在 IR 损伤中也有保护作用。在体外研究 SIRT3过表达在心肌细胞暴露于缺氧显示保护细胞损伤通过下调凋亡涉及 Ku70和 Bax。127在体内也可以看到同样的作用,与野生型小鼠相比,SIRT3基因敲除小鼠更容易受到 IR 损伤,损伤增加,线粒体功能损伤减少。121 SIRT4在心肌细胞中的过表达通过降低 caspase 活性和细胞凋亡来提高其存活率,而在同一细胞中敲除 SIRT4则导致存活率降低和细胞凋亡的诱导。与野生型小鼠相比,125只 SIRT5基因敲除小鼠在 IR 损伤后梗死面积增大,并且一种琥珀酸脱氢酶抑制剂对此损伤有保护作用,这意味着 SIRT5在 IR 损伤背景下调节心脏中的蛋白琥珀酸化作用。128体外研究也支持 SIRT5在防止 IR 损伤方面的作用,至少部分是通过减少细胞凋亡。129

Little is known about the role of the nuclear sirtuins SIRT6 and SIRT7 and the other cytoplasmic sirtuin SIRT2 in IR injury. One study showed that cardiomyocytes isolated from mice overexpressing SIRT6 had less damage when exposed to hypoxia than those isolated from wild-type mice, via a downregulation of apoptosis and oxidative stress through modulation of B-cell lymphoma 2, NFκB, phosphorylated Akt, and phosphorylated-5′ adenosine monophosphate-activated protein kinase (AMPK).130 An in vitro study suggested that SIRT2 may play a contributing role in IR injury with downregulation of SIRT2 protecting against hypoxia in H9c2 cells.131 This supports other evidence suggesting that SIRT2 acts as a negative regulator of biological stress.132

细胞核 sirtuins SIRT6和 SIRT7以及其他细胞质 sirtuin SIRT2在 IR 损伤中的作用尚不清楚。一项体外研究表明,与野生型小鼠相比,从过度表达 SIRT6的小鼠分离出的心肌细胞在缺氧环境下损伤较小,这是通过调节 b 细胞淋巴瘤2、 nf b、磷酸化 Akt 和磷酸化5′ AMP活化蛋白激酶(AMPK)而导致的细胞凋亡和细胞凋亡的下调

Cardiac-specific overexpression of NAMPT in mice results in an expected increase in cardiac NAD+ levels and protection against IR injury.122 In addition, ischemic preconditioning, which is known to reduce damage to subsequent IR injury, seems to induce protection at least in part through NAMPT upregulation.65 NAMPT knockout mice show no protection against IR injury with preconditioning.65 Increasing NAD+ levels with the precursor NMN also protects against IR injury.65 PARP inhibitors also protect against IR injury in a variety of animal models,133 possibly through increased NAD+ levels. The CD38 inhibitor luteolinidin also prevented left ventricular contractile and endothelial dysfunction after IR injury in isolated rat hearts.88

此外,缺血预处理,众所周知可以减少随后 IR 损伤,似乎至少部分地通过 NAMPT 上调来诱导保护。65 NAMPT 基因敲除小鼠在预处理下对 IR 损伤没有保护作用。65增加 NAD + 水平与前体 NMN 也可以保护 IR 损伤。65 PARP 抑制剂也可以保护多种动物模型的 IR 损伤,133可能是通过增加 NAD + 水平。CD38抑制剂木犀草素还可以预防 IR 损伤大鼠离体心脏后左室收缩和内皮功能障碍

Overall, sirtuins and NAD+ seem to have a strongly protective role in IR injury. There is the potential for the development of STACs or NAD boosting therapeutics for use during cardiac surgery or to attenuate damage postmyocardial infarction in older patients.

总的来说,去乙酰化酶和 NAD + 似乎在 IR 损伤中有很强的保护作用。在心脏外科手术或者减轻老年患者心肌梗死后的损伤方面,存在开发 STACs 或 NAD 促进疗法的潜力。

Hypertrophy, Fibrosis, and Heart Failure

肥大、纤维化和心力衰竭

Aging is associated with distinct structural changes in the heart, including increased fibrosis, left ventricular hypertrophy, and dilation.134–136 Hypertrophy and fibrosis in the aging heart cause systolic and diastolic dysfunctions and can ultimately result in heart failure.134–136 Age-related hypertension can contribute to the development of hypertrophy and heart failure in humans. Mice do not naturally develop age-related hypertension, so this is modeled in rodents with interventions including TAC that causes pressure overload, angiotensin II exposure, doxorubicin exposure, transgenic cardiomyopathy models, diabetic cardiomyopathy, and other stress-induced cardiomyopathy models.

老化与心脏的明显结构变化有关,包括增加的纤维化、左心室肥大和扩张。老化心脏的肥大和纤维化会导致收缩和舒张功能障碍,并最终导致心力衰竭。小鼠不会自然发生与年龄有关的高血压,因此这是在啮齿动物身上建立的模型,其干预措施包括引起压力超负荷的 TAC、暴露于血管紧张素 II、暴露于阿霉素、转基因心肌病模型、糖尿病心肌病模型和其他应激性心肌病模型。

SIRT1 has apparently opposing roles in age-related structural changes of the heart. Several mouse studies have observed the development of cardiac hypertrophy in mice with SIRT1 overexpression,137 with one study showing the degree of impairment was dependent on the degree of overexpression.138 High levels of SIRT1 overexpression (20-fold) resulted in dilated cardiomyopathy while moderate overexpression (6.8-fold) caused diastolic dysfunction, and low overexpression (3.2-fold) resulted in normal function at baseline but the development of cardiac dysfunction with pressure overload.138 Knockout of either SIRT1 or peroxisome proliferator-activated receptor α (PPARα) reduced hypertrophy in a TAC mouse study while the overexpression of both proteins exacerbated it,139 ostensibly because of upregulation of estrogen-related receptors and resulting mitochondrial dysfunction.139

SIRT1在与年龄相关的心脏结构改变中具有明显的对立作用。一些小鼠研究观察了 SIRT1过表达小鼠心肌肥大的发展,137个研究表明损伤程度依赖于过表达的程度。138 SIRT1高水平过表达(20倍)导致扩张型心肌病,中度过表达(6.8倍)导致舒张功能障碍,低水平过表达(3.2倍)导致基线功能正常,但心功能障碍伴压力超负荷。138. 在一项 TAC 小鼠研究中,SIRT1或过氧化物酶体增殖物活化受体基因敲除减少了肥大,而这两种蛋白的过度表达加剧了肥大,表面上是因为雌激素相关受体上调和线粒体功能障碍。139

Conversely, SIRT1 can also have a protective function (Figure 4). Another study exploring levels of cardiac-specific SIRT1 overexpression on age-related remodeling in 18-month-old mice found that low to moderate overexpression (2.5–7.5 fold) protected against age-related hypertrophy, fibrosis, and cardiac dysfunction while only a high level of overexpression (12.5-fold) resulted in cardiomyopathy and hypertrophy.140 The authors suggest that the detrimental effect of a high level of SIRT1 overexpression is because of induction of mitochondrial dysfunction,140 which may also contribute to hypertrophic damage in the context of TAC pressure overload and increased SIRT activity.138Cardiomyocytes with SIRT1 activation either genetically or with resveratrol were protected against phenylephrine-induced hypertrophy and related inflammation. Interestingly, in direct opposition to that seen above, the inhibition of PPARα stopped this protective effect.141 The same study also showed that SIRT1 overexpression in mice protected against isoproterenol-induced hypertrophy.141 Mouse studies using either stress-induced or diabetes mellitus models of cardiomyopathy observed that SIRT1 knockout increased hypertrophy and decreased cardiac function, and that treatment with either the sirtuin activator STAC-3 or resveratrol was protective against this hypertrophy.72,142 Consistent with this, resveratrol treatment in rat or hamster models of heart failure and cardiomyopathy also prevented hypertrophy and a decline in cardiac function although the exact target of resveratrol is difficult to prove without the use of SIRT1 knockouts.67–71,73


相反,SIRT1也有保护作用(图4)。另一项研究探索了心脏特异性 SIRT1过度表达对18个月大小鼠年龄相关重塑的影响,发现低至中度过度表达(2.5-7.5倍)可以防止年龄相关性肥大、纤维化和心功能障碍,而仅高水平的过度表达(12.5倍)导致心肌病和肥厚。140作者认为高水平的 SIRT1过表达的有害影响是由于线粒体功能障碍的诱导,140这也可能有助于在 TAC 压力超负荷和 SIRT 活性增加的背景下的肥大性损伤。138个具有 SIRT1活性的心肌细胞,无论是基因激活还是白藜芦醇激活,均能保护苯肾上腺素所致的心肌肥大及相关炎症。有趣的是,与上述结果相反,ppar 的抑制作用阻止了这种保护作用。141同一研究还表明,SIRT1在小鼠体内的过度表达对异丙肾上腺素诱导的肥大具有保护作用。141小鼠应激诱导或糖尿病心肌病模型研究发现 SIRT1基因敲除增加心肌肥厚和降低心功能,用 sirtuin 激活剂 STAC-3或白藜芦醇治疗都能保护心肌肥厚。72,142与此相一致的是,白藜芦醇在大鼠或仓鼠心力衰竭和心肌病模型中的治疗也可以防止心肌肥大和心功能下降,尽管如果不使用 SIRT1基因敲除剂,白藜芦醇的确切目标很难证实。67-7173

The conflicting roles of SIRT1 in these studies imply a potentially different effect of SIRT1 on cardiac remodeling in different contexts and models. Investigation of the role of sirtuins in more clinically relevant models of cardiac aging, or studies in aging humans themselves, will be essential. Importantly, the one study discussed above that did use naturally aging mice found a protective effect of low to moderate SIRT1 overexpression on hypertrophy.140 More studies are required to fully understand the complex effects of SIRT1 in cardiomyopathy and hypertrophy in animal models and humans.

在这些研究中,SIRT1的相互冲突的作用表明,在不同的环境和模型中,SIRT1对心脏重构的作用可能是不同的。研究去乙酰化酶在更多临床相关的心脏衰老模型中的作用,或者研究衰老人类自身,将是必不可少的。重要的是,上面讨论的一项研究确实使用了自然衰老的小鼠,发现了低到中度 SIRT1过度表达对心肌肥厚的保护作用。

SIRT3 has a clear protective role in cardiac hypertrophy. Doxorubicin-induced cardiomyopathy, TAC-induced hypertrophy, and a Friedreich ataxia model of cardiomyopathy all resulted in reduced SIRT3 levels, which were associated with hyperacetylation of mitochondrial proteins.62,143,144 SIRT3 knockout mice develop hypertrophy and fibrosis as they age as a result of increased mitochondrial permeability transition pore opening (Figure 1) and transforming growth factor-β1 signaling.145,146 SIRT3 knockout mice are also more sensitive to the hypertrophic effects of TAC, angiotensin II,144,145,147 doxorubicin,143,148 diabetes mellitus,149 and isoprotenerol150 than wild-type mice. SIRT3 overexpression results in resistance to hypertrophy-inducing stimuli, as a result of increased FOXO3a, manganese superoxide dismutase, oxoguanine glycosylase 1, parkin, and catalase activation.143,147,149 HFD is also associated with hypertrophy and cardiac dysfunction which is accompanied by a decrease in cardiac SIRT3. Moreover, SIRT3 knockout mice with HFD had greater cardiac dysfunction than HFD-fed wild-type mice.151 The known protective effects of resveratrol on hypertrophy and fibrosis may be as a result of both SIRT1 and SIRT3 activation as the protective effects of resveratrol were not observed in SIRT3 knockout mice in one study.36 Honokiol is a polyphenolic compound that is thought to activate SIRT3. Honokiol treatment in mice exposed to pressure overload and drug-induced heart failure prevented hypertrophy and fibrosis,40 as well as the associated mitochondrial damage and cell death.41

SIRT3对心肌肥大有明显的保护作用。多柔比星诱导的心肌病、 tac- 诱导的心肌肥厚和 Friedreich 型心肌病模型均导致 SIRT3水平降低,这与线粒体蛋白高乙酰化有关。62,143,144 SIRT3基因敲除小鼠由于线粒体通透性转换孔开口增加(图1)和转化生长因子 -1信号传导增加,随着年龄的增长,发生肥大和纤维化。145,146 SIRT3基因敲除小鼠对 TAC,angiotensin II,144,145,147阿霉素,143,148糖尿病,149和 isoprotenerol150的肥大效应也比野生型小鼠更敏感。SIRT3的过度表达导致抵抗肥大诱导刺激,由于增加 FOXO3a,锰超氧化物歧化酶,氧鸟嘌呤糖苷酶1,parkin,和过氧化氢酶激活。143,147,149 HFD 也与肥大和心脏功能障碍有关,伴随着心脏 SIRT3的减少。已知白藜芦醇对肥大和纤维化的保护作用可能是 SIRT1和 SIRT3激活的结果,因为在一项研究中没有观察到白藜芦醇对 SIRT3基因敲除小鼠的保护作用。和厚朴酚治疗暴露于压力超负荷和药物引起的心力衰竭的小鼠,防止了心肌肥大和纤维化,40以及相关的线粒体损伤和细胞死亡

The role of the other sirtuins in cardiac hypertrophy and fibrosis has not been as extensively studied. SIRT2 knockout mice have increased hypertrophy and fibrosis and decreased systolic function compared to wild-type mice.152 Moreover, cardiac-specific SIRT2 overexpression protected against angiotensin II–induced hypertrophy by activating liver kinase B1, which ultimately resulted in maintenance of AMPK levels in hypertrophy.152 SIRT4 seems to contribute to remodeling, with SIRT4 knockout mice having reduced fibrosis and hypertrophy in response to angiotensin II, and cardiac-specific SIRT4 overexpression increasing hypertrophy and reducing cardiac function.153 SIRT5 prevents age-related hypertrophy with aging SIRT5 knockout mice displaying more fibrosis, hypertrophy, and systolic dysfunction than age-matched wild types.154 SIRT6 knockout mice have increased hypertrophy while overexpression of SIRT6 was associated with protection against hypertrophic stimuli in mice.155 Overexpression of nicotinamide mononucleotide adenylyltransferease 2 in rat cardiomyocytes to increase NAD+ protected against hypertrophy in a SIRT6- but not SIRT1-dependent manner, further suggesting a protective role of SIRT6.156 Finally, SIRT7 knockout in mice results in hypertrophy, fibrosis, inflammation, systolic dysfunction, and increased apoptosis,157,158 indicating a protective role of SIRT7 against cardiomyopathy and hypertrophy as well.

其他去乙酰化酶在心肌肥大和纤维化中的作用尚未被广泛研究。与野生型小鼠相比,SIRT2基因敲除小鼠有增加的肥厚和纤维化以及降低的收缩功能。152此外,心脏特异性 SIRT2过度表达通过激活肝激酶 B1保护血管紧张素 II 诱导的心肌肥大,最终导致心肌肥大中 AMPK 水平的维持。152 SIRT4似乎有助于重塑,SIRT4基因敲除小鼠对血管紧张素 II 的反应导致纤维化和肥大减少,而心脏特异性 SIRT4过表达增加肥大和降低心功能。与年龄匹配的野生型小鼠相比,老化的 SIRT5基因敲除小鼠表现出更多的纤维化、肥大和收缩功能障碍,153 SIRT5可以预防与年龄相关的肥大。154只 SIRT6基因敲除小鼠肥大增加,而 SIRT6基因过度表达与小鼠对肥大性刺激的保护作用有关。155大鼠心肌细胞过度表达烟酰胺单核苷酸腺苷转移酶2,增加 NAD + ,以 SIRT6-而非 sirt1依赖的方式保护心肌肥大,进一步提示 SIRT6.156的保护作用。最后,SIRT7基因敲除导致小鼠心肌肥大、纤维化、炎症、收缩功能障碍和细胞凋亡增加,157,158表明 SIRT7对心肌病和心肌肥大具有保护作用。

Several studies suggest that increasing NAD+ may protect against hypertrophy. Increasing NAD+ in mice by either dosing with NMN or overexpressing NAMPT prevented hypertrophy induced by TAC and improved cardiac function63 by increasing energy production in the mitochondria and reducing mitochondrial permeability transition pore opening.63 The addition of NAD+ prevented isoproterenol-induced hypertrophy in mice, and interestingly, this was mediated by SIRT3, but not SIRT1, through activation of liver kinase B1-AMPK signaling.150 NMN treatment protected against cardiac dysfunction in a Friedreich ataxia cardiomyopathy mouse model in a SIRT3-dependent manner62 and increased cardiac function in Ndufs4 knockout mice exposed to pressure overload.64 NR treatment also reduced inflammation and fibrosis in aged MDX mice, a muscular dystrophy model that develops cardiomyopathy.66 Finally, PARP inhibitors protected against hypertrophy and improved cardiac function in several rodent models,133 possibly in part by increasing NAD+levels.

一些研究表明,增加 NAD + 可能保护对抗肥大。增加小鼠脑内 NAD + 的剂量或过度表达 NAMPT 均可防止 TAC 诱导的心肌肥大,并通过增加线粒体能量产生和减少线粒体通透性转换孔开放而改善心功能63。63. NAD + 的加入可以阻止异丙肾上腺素诱导的小鼠肥大,有趣的是,这是通过 SIRT3介导的,而不是通过激活肝激酶 B1-AMPK 信号转导的 SIRT1。150 NMN 对 sirt3依赖性 manner62的 Friedreich 共济失调性心肌病小鼠模型的心功能障碍有保护作用,并增加了 Ndufs4基因敲除小鼠压力超负荷后的心功能。64 NR 治疗还可以减少老龄 MDX 小鼠的炎症和纤维化,这是一种发展为心肌病的肌肉萎缩症模型。66最后,PARP 抑制剂在一些啮齿动物模型中能够保护心肌肥大和改善心功能,133可能部分是通过提高 NAD + 水平。

The role of sirtuins and NAD+ in heart failure, rather than remodeling, has not been as extensively studied. Levels of SIRT1 increase in failing hamster,71 rat,68 mouse,140 and dog hearts,159 but whether this increase is cardioprotective or contributes to the development of heart failure is not clear. The association between heart failure and the other sirtuins is not well understood although one study found reduced SIRT6 expression in failing human hearts.155 Failing hearts also have extensive mitochondrial hyperacetylation that may contribute to dysfunction in heart failure,160 and NAD+ levels are reduced in failing mouse and human hearts.63,160

去乙酰化酶和 NAD + 在心力衰竭中的作用,而不是重塑,还没有被广泛研究。在衰竭的仓鼠,71只大鼠,68只小鼠,140只和狗的心脏中,SIRT1的水平增加,159,但是这种增加是否具有心脏保护作用或者是否导致心脏衰竭尚不清楚。虽然一项研究发现 SIRT6在衰竭的心脏中的表达减少,但心力衰竭和其他去乙酰化酶之间的联系还没有得到很好的理解

Overall, moderately increasing SIRT1 activity, increasing SIRT3 activity, or boosting NAD+ levels seem to be promising approaches for protection against age-related hypertrophy and fibrosis. More research in clinically relevant models of heart aging is needed, however, to understand the potentially detrimental effects of high overexpression of SIRT1.

总的来说,适度增加 SIRT1的活性,增加 SIRT3的活性,或者增加 NAD + 的水平似乎是预防年龄相关性肥大和纤维化的有希望的方法。然而,为了了解 SIRT1高表达的潜在不利影响,还需要对心脏衰老的临床相关模型进行更多的研究。

Arrhythmias

心律失常

The risk of atrial fibrillation and other types of arrhythmias increases significantly with age.135 The role of sirtuins and NAD+ in arrhythmias has been minimally investigated. A recent study showed that SIRT1 deacetylases the voltage-gated Na+ channel (Nav1.5), which is necessary for normal cardiac electrophysiology, to increase its activity. Cardiac-specific SIRT1 knockout mice had decreased Nav1.5 expression, which resulted in abnormal cardiac conduction.161One study in BubR1 knockout mice, which are short-lived in part because of defective cardiac electrophysiology, showed a potential role of NAD+ and SIRT2 in treating arrhythmias. They found that either overexpressing SIRT2 or increasing NAD+ levels with NMN increased BubR1 and partly reversed the repolarization defects observed.162 Given the association between reduced NAD+ and sirtuin activity in the heart with age and the increased risk of arrhythmias, this is an area that warrants further research.

随着年龄的增长,心室颤动和其他类型心律失常的风险显著增加。最近的一项研究表明,SIRT1去乙酰化能够增强正常心肌细胞的电压门控性 Na + 通道(Nav1.5)的活性,而该通道是正常心肌电生理学所必需的。心脏特异性 SIRT1基因敲除小鼠减少了 Nav1.5的表达,从而导致心脏传导异常。在 BubR1基因敲除小鼠中的一项研究表明,NAD + 和 SIRT2在治疗心律失常方面具有潜在的作用。 BubR1基因敲除小鼠存活时间较短,部分原因是心脏电生理学缺陷。他们发现过度表达 SIRT2或增加 NAD + 水平而 NMN 增加了 BubR1并部分逆转了观察到的复极缺陷。

Hypertension

高血压

Hypertension is a risk factor for other cardiovascular diseases and the risk of hypertension increases with age, especially in women.163,164 Few studies have explored the effects of the sirtuins on hypertension. Angiotensin II exposure, which is a commonly used model of hypertrophy in mice, also causes hypertension although most studies of angiotensin II–induced hypertrophy discussed above did not investigate blood pressure changes. One study of SIRT1 overexpression in the context of angiotensin II found that SIRT1 protected against the systolic blood pressure increase seen in wild-type mice.165 In addition, a study in rats with spontaneous pulmonary artery hypertension found that they had reduced SIRT3 expression and that SIRT3 overexpression prevented the development of hypertension.166Polymorphisms in SIRT3 were also associated with pulmonary artery hypertension in patients.166 More research in this area will identify whether boosting sirtuins or NAD+ may protect against hypertension in aging.

高血压是其他心血管疾病的危险因素,高血压的危险随着年龄的增长而增加,尤其是女性。血管紧张素 II 暴露是一种常用的小鼠肥大模型,也可引起高血压,尽管以上讨论的大多数血管紧张素 II 诱导肥大的研究没有探讨血压的变化。此外,一项对自发性肺动脉高血压大鼠的研究发现,SIRT3的过度表达减少了 SIRT3的表达,并且 SIRT3的过度表达阻止了高血压的发展。 SIRT3的166个多态性也与肺动脉高血压有关。

Diabetes Mellitus, Glucose/Insulin Dysregulation, and Metabolic Syndrome

糖尿病,葡萄糖/胰岛素失调,和代谢症候群

The metabolic syndrome is a set of risk factors for cardiovascular diseases including obesity, diabetes mellitus, increased LDL levels, increased triglyceride (TG) levels, and hypertension.167,168 Type 2 diabetes mellitus is characterized by high blood glucose levels, low levels of insulin, and insulin resistance. The risk of diabetes mellitus is increased by obesity and a lack of exercise, and diabetes mellitus is associated with an increased risk of cardiovascular disease, stroke, and kidney failure.169 Increasing age is a significant risk factor for insulin resistance and impaired glucose tolerance.170–172 The role of sirtuins in glucose and insulin control, obesity, and the development and prevention of diabetes mellitus has been well explored, at least for SIRT1, 3, 4, and 6. A variety of animal models are used to study diabetes mellitus and insulin resistance including aging mice, transgenic mouse models of diabetes mellitus, such as db/db, and the induction of obesity and diabetes mellitus with an HFD. Human studies are limited, but a specific SIRT1 mutation was associated with type 1 diabetes mellitus in one patient study,173 and low SIRT1 has been associated with insulin resistance in the offspring of those with type 2 diabetes mellitus.174 Two human studies found associations between SIRT3 polymorphisms and the metabolic syndrome, suggesting a role of SIRT3 in this syndrome in humans166,175

代谢症候群是一组心血管疾病的危险因素,包括肥胖、糖尿病、低密度脂蛋白水平升高、甘油三酯水平升高和高血压。167,1682型糖尿病是拥有属性高血糖水平、低胰岛素水平和胰岛素抵抗。年龄增长是胰岛素抵抗和胰岛素抵抗的一个重要危险因素,sirtuins 在葡萄糖和胰岛素控制、肥胖以及发展和预防糖尿病方面的作用已经得到了很好的探索,至少对于 SIRT1、3、4和6来说是如此。多种动物模型被用来研究糖尿病和胰岛素抵抗,包括老龄小鼠,转基因小鼠的糖尿病,如 db/db,诱导肥胖和 HFD 的糖尿病。人类的研究是有限的,但是在一个病人的研究中,一个特定的 SIRT1突变与1型糖尿病有关,173和低 SIRT1已经与2型糖尿病患者的后代的胰岛素抵抗有关

SIRT1 transgenic overexpressors fed a diet high in fat and cholesterol have better glucose homeostasis than wild-type mice fed the same diet but with no difference in body weight.12,13,97 SIRT1-overexpressing mice fed a standard diet also show increased glucose tolerance, which is accompanied by reduced cholesterol, reduced fat mass, and lower body weight.176 SIRT1 overexpression in the db/db diabetic mouse model also improved glucose tolerance and reduced hepatic glucose production.13 Pancreatic β-cell–specific overexpression of SIRT1 was associated with increased insulin secretion and improved glucose tolerance, even as the mice aged.177 Both mice and rhesus monkeys with insulin resistance induced by an HFD had increased insulin sensitivity when SIRT1 activity was increased with resveratrol or SRT1720 treatment.79–83 Mice fed a standard diet and dosed with the SIRT1 activators SRT2104 or SRT1720 also had increased insulin sensitivity.16,17 The role of reduced SIRT1 function in mice is less clear. One study found that SIRT1 knockout mice displayed reduced basal and glucose-stimulated insulin levels as a result of upregulation of UCP (uncoupling protein) 2 expression.178 Another study, however, showed that on a standard diet, liver-specific SIRT1 knockout mice had no change in insulin or glucose modulation and that on an HFD, they maintained insulin sensitivity, implying a role of SIRT1 in contributing to insulin resistance in this model.179

SIRT1转基因高表达小鼠喂养高脂肪和高胆固醇的饮食有更好的葡萄糖稳态比野生型小鼠喂养相同的饮食,但没有不同的体重。12,13,97 sirt1-过度表达的小鼠在标准饮食中也表现出增加的葡萄糖耐量,伴随着胆固醇降低,脂肪减少和体重降低。176 SIRT1在 db/db 糖尿病小鼠模型中的过表达也改善了葡萄糖耐量和降低了肝脏葡萄糖产量。13即使在老龄小鼠中,SIRT1的胰腺细胞特异性过表达也与胰岛素分泌增加和糖耐量改善有关。177 HFD 诱导的胰岛素抵抗小鼠和恒河猴在白藜芦醇或 SRT1720增加 SIRT1活性时,胰岛素敏感性均增加。79-83小鼠喂食标准饲料并服用 SIRT1激活剂 SRT2104或 SRT1720也增加了胰岛素敏感性。16,17 SIRT1功能下降在小鼠中的作用尚不清楚。然而,另一项研究表明,在标准饮食中,肝特异性 SIRT1基因敲除小鼠在胰岛素或葡萄糖调节方面没有变化,而在 HFD 中,它们保持了胰岛素敏感性,这意味着 SIRT1在该模型中有助于胰岛素抵抗

Although overexpression of SIRT1 in high caloric exposure generally acts to decrease glucose and increase insulin response, increased SIRT1 in fasting seems to increase glucose production. Acute SIRT1 knockout in the liver of fasted mice actually resulted in increased insulin sensitivity, decreased serum glucose, and decreased glucose production, and overexpression reversed these effects.180 In vitro studies show that SIRT1 negatively regulates glycolysis through phosphoglycerate mutase 1 and that in fasted cells there is increased SIRT1 activity and thus reduced glucose breakdown.181 Fasting in mice also resulted in increased SIRT1 modulation of the glycolytic and gluconeogenesis pathways via FOXO1 and PGC1α to potentially increase glucose levels.22 Thus, there is clearly a complex and potentially tissue-specific relationship between nutritional state, SIRT1, and insulin and glucose regulation that requires further research.

虽然 SIRT1在高热量暴露时过度表达通常会降低血糖和增加胰岛素反应,但在空腹时增加 SIRT1似乎会增加血糖的产生。禁食小鼠肝脏 SIRT1基因敲除实际上导致胰岛素敏感性增加,血糖降低,葡萄糖产量下降,过度表达逆转了这些效应。180. 体外研究表明,SIRT1通过磷酸甘油酸突变酶1负性调节糖酵解,而在禁食细胞中,SIRT1活性增加,从而减少葡萄糖分解。181小鼠禁食后,通过 FOXO1和 pgc1增强了 SIRT1对糖酵解和糖异生途径的调节,从而可能提高了葡萄糖水平。因此,营养状态、 SIRT1、胰岛素和葡萄糖调节之间显然存在着复杂的、潜在的组织特异性关系,需要进一步的研究。

Unlike SIRT1, SIRT3 knockout mice fed a high-cholesterol diet gained more weight but had the same glucose tolerance as wild-type mice.101 One study of HFD-fed SIRT3 knockout mice found increased fatty acid oxidation, implying that SIRT3 may act to protect against insulin resistance in high calorie environments by decreasing fatty acid oxidation.182Interestingly, SIRT3 seems to have the opposite effect in low calorie environments as SIRT3 knockout mice have decreased levels of fatty acid oxidation in fasting.24 SIRT4 knockout mice have upregulation of fatty acid oxidation and metabolism,25,183,184 which results in protection against diet-induced obesity.185 SIRT4 knockout mice also have increased insulin secretion in response to amino acids,25 which results in insulin resistance and glucose intolerance.186Interestingly, SIRT4 knockout mice also have increased SIRT1 activity, so there are likely several sirtuin pathways involved in the regulation of glucose and insulin homeostasis.183

与 SIRT1不同,SIRT3基因敲除小鼠喂食高胆固醇饮食后体重增加更多,但与野生型小鼠有相同的葡萄糖耐量。101对 HFD-fed SIRT3基因敲除小鼠的一项研究发现,脂肪酸氧化增加,这意味着 SIRT3可能通过减少脂肪酸氧化,在高热量环境中起到保护胰岛素抵抗的作用。182有趣的是,SIRT3在低热量环境中似乎有相反的效果,因为 SIRT3基因敲除小鼠在禁食时脂肪酸氧化水平下降。24只 SIRT4基因敲除小鼠脂肪酸氧化和代谢上调,25,183,184对饮食诱导的肥胖有保护作用。185 SIRT4基因敲除小鼠对氨基酸的反应也增加了胰岛素的分泌,导致胰岛素抵抗和葡萄糖耐受不良。186有趣的是,SIRT4基因敲除小鼠也增加了 SIRT1的活性,所以很可能有几条去乙酰化酶通路参与了葡萄糖和胰岛素稳态的调节。183

Whole-body SIRT6 knockout mice die prematurely from hypoglycemia. The mechanism seems to be increased AKT activation and reduced insulin-like growth factor-1 levels, which results in upregulation of glucose transporters and increased glucose uptake in skeletal muscle and brown adipose tissue.187–189 SIRT6 knockout mice also have increased glucose production as normally SIRT6 downregulates hepatic glucose production via PGC1α190 as well as increased glycolysis, possibly through increased activity of hypoxia-inducible factor-1α.189,191 Interestingly, overexpression of SIRT6 improved glucose homeostasis in aging mice15 and increased glucose tolerance and insulin sensitivity in the context of an HFD, along with a reduction in visceral fat.11 The authors suggest that the HFD caused defective insulin secretion as a result of increased fat and inflammatory cells in the pancreas and that SIRT6 overexpression improved insulin sensitivity by reducing this inflammatory pancreatic infiltration.11 Neural-specific SIRT6 knockout mice develop obesity overtime implying that SIRT6 may act as a central regulator of growth and obesity.192 As such, SIRT6 may be a promising target for therapeutics to modulate obesity, increase insulin sensitivity, and reduce glucose levels in patients. SIRT7 may also have a role in regulating glucose levels as SIRT7 knockout mice were resistant to glucose intolerance.193 Supplementation of mice on an HFD with NR increased insulin sensitivity and reduced fat mass compared with HFD alone. Interestingly, NR also increased the activity of SIRT2 and SIRT3.59Similarly, supplementation with NMN also prevented the insulin resistance and glucose intolerance associated with an HFD in mice and improved glucose tolerance in aging mice.194 Finally, treatment with the CD38 inhibitor apigenin in mice with diet-induced obesity resulted in increased NAD+ levels, as well as protection against glucose dysregulation.53

SIRT6基因敲除小鼠因低血糖过早死亡。其机制似乎是增加 AKT 激活和降低胰岛素样生长因子 -1水平,导致葡萄糖转运蛋白上调和骨骼肌和褐色脂肪组织葡萄糖摄取增加。SIRT6基因敲除小鼠在正常情况下通过 pgc1190下调肝脏葡萄糖产量,并可能通过增加缺氧诱导因子 -1的活性而增加糖酵解,从而提高了葡萄糖产量。189,191有趣的是,SIRT6的过度表达改善了老化过程中的葡萄糖稳态,增加了 HFD 患者的葡萄糖耐量和胰岛素敏感性,同时减少了内脏脂肪。11. 作者认为,HFD 由于胰腺脂肪和炎症细胞增加而导致胰岛素分泌缺陷,SIRT6的过度表达通过减少胰腺炎性浸润而改善胰岛素敏感性。11. 神经特异性 SIRT6基因敲除小鼠超时发生肥胖,这意味着 SIRT6可能是生长和肥胖的中枢调节因子。192因此,SIRT6可能是调节肥胖、增加胰岛素敏感性和降低患者血糖水平的一个有希望的治疗目标。SIRT7也可能在调节葡萄糖水平方面发挥作用,因为 SIRT7基因敲除小鼠对葡萄糖耐受不良有抵抗力。有趣的是,NR 也增加了 SIRT2和 SIRT3.59的活性,同样,NMN 的补充也可以防止小鼠的胰岛素抵抗和与 HFD 相关的葡萄糖耐受不良,并改善老龄小鼠的葡萄糖耐量

Overall sirtuins seem to have a complex but generally protective effect on obesity, but whether this effect is related to or independent from effects on insulin and glucose regulation is still not known. Boosting NAD+ levels or increasing SIRT1 and SIRT6 activity in the context of the metabolic syndrome, type 2 diabetes mellitus, and insulin resistance could be an important therapeutic approach for preventing and treating these diseases in aging.

总的来说去乙酰化酶似乎对肥胖有一种复杂但普遍的保护作用,但是这种作用是否与胰岛素和葡萄糖调节有关还是独立的尚不清楚。在代谢症候群、2型糖尿病和胰岛素抵抗的背景下,提高 NAD + 水平或增加 SIRT1和 SIRT6活性可能是预防和治疗这些老年疾病的重要治疗方法。

Dyslipidemia

血脂异常

Dyslipidemia is characterized by abnormal levels of lipids, including TGs and cholesterol, in the blood. The most common of these abnormalities in the elderly is hypercholesterolemia that is an increased level of LDL cholesterol.195,196 The role of sirtuins and NAD+ in dyslipidemia has not been well characterized. SIRT1 has a role in cholesterol homeostasis as a positive regulator of the cholesterol-sensing proteins, liver X receptors.197 SIRT1 knockout results in reduced liver X receptor expression and reduced high-density lipoprotein and TG lipid levels, implying a protective role of SIRT1 in increasing the levels of beneficial high-density lipoprotein cholesterol.197 The role of SIRT1 in lipid homeostasis also seems to depend on the nutritional state of the mice. Acute SIRT1 knockout in the liver of fasted mice results in decreased serum cholesterol levels and increased liver cholesterol.180 The opposite role for SIRT1 was seen on standard or HFD, however, where SIRT1 overexpression resulted in decreased serum cholesterol levels.176,198

血脂异常是指拥有属性血液中脂质水平异常,包括 TGs 和胆固醇。这些异常在老年人中最常见的是高胆固醇血症,即低密度脂蛋白胆固醇水平升高。SIRT1作为胆固醇敏感蛋白质肝 x 受体的积极调节者,在胆固醇稳态中发挥作用。 SIRT1基因敲除导致肝X受体表达减少,高密度脂蛋白和 TG 脂质水平降低,这意味着 SIRT1在增加有益高密度脂蛋白胆固醇水平方面发挥保护作用。在禁食小鼠的肝脏中,SIRT1的急性基因敲除导致血清胆固醇水平降低和肝脏胆固醇升高

SIRT3 knockout mice with HFD exposure develop hyperlipidemia, implying a role of SIRT3 in maintaining lipid homeostasis.24 SIRT4 also has a role in lipid metabolism by regulating mast cell degranulating peptide activity.185 SIRT6 plays a role in negatively regulating glycolysis and TG synthesis191 and may also have a role in protecting against increased LDL cholesterol levels.199 SIRT6 knockout mice have increased LDL while SIRT6 overexpressing mice fed an HFD have lower LDL and TG levels than wild-type mice.11,199 NR in HFD-fed mice was associated with reduced LDL cholesterol levels compared with HFD alone.59 Niacin, which is a collective term for nicotinamide and nicotinic acid, has for many years been used as a treatment for hypercholesterolemia,200 but the mechanism of this protection is still not known.201 NAD+-dependent activation of sirtuins is a possible mechanism,202 but the effect may also be driven by NAD+-independent activation of the G-coupled receptor GPR109A.201

SIRT3基因敲除小鼠在 HFD 暴露后发生高脂血症,提示 SIRT3在维持脂质平衡中的作用。24 SIRT4还通过调节肥大细胞去颗粒化肽的活性在脂质代谢中发挥作用。185 SIRT6在糖酵解和甘油三酯合成中起负调节作用,也可能在保护低密度脂蛋白胆固醇水平增加中起作用。199只 SIRT6基因敲除小鼠与野生型小鼠相比,高表达 SIRT6的 HFD 小鼠低密度脂蛋白和甘油三酯水平明显降低。与单独使用 HFD 相比,高密度脂蛋白饲养的小鼠血清11,199硝酸还原酶(NR)水平降低。烟酸,是烟酰胺和烟酸的统称,多年来一直被用作高胆固醇血症的治疗药物,但这种保护作用的机制仍不清楚。201 NAD + 依赖性激活 sirtuins 是一种可能的机制,202但这种效应也可能是由 NAD + 独立激活 g 受体 GPR109A 所致。201

NAD+ and sirtuin boosters may have beneficial roles in treating dyslipidemia, especially in the context of Western diets, but more research is required to fully understand the mechanisms behind this protection and the role of each of the sirtuins in lipid homeostasis.

NAD + 和 sirtuin 助推剂可能在治疗血脂异常方面有有益的作用,特别是在西方饮食的背景下,但需要更多的研究来充分了解这种保护背后的机制和每一种 sirtuin 在脂质稳态中的作用。

Clinical Trials of Molecules to Modulate Sirtuins and NAD+ in Cardiovascular and Metabolic Diseases

调节去乙酰化酶和 NAD + 分子在心血管和代谢性疾病中的临床研究

The use of both STACs and NAD+ boosters in cardiovascular and metabolic diseases has shown beneficial effects in a variety of animal models (Table 2). Given the preclinical evidence for benefits of sirtuins and NAD+ in preventing and treating cardiovascular and metabolic diseases, many researchers recognize the potential of these pathways as medicines. As a result, there are a growing number of human trials of sirtuin and NAD+-boosting drugs, some of which are showing protective effects in cardiovascular and metabolic diseases (Table 3).

在心血管和代谢性疾病中使用 STACs 和 NAD + 助推剂已经在多种动物模型中显示出有益的效果(表2)。鉴于去乙酰化酶和 NAD + 在预防和治疗心血管和代谢性疾病方面的益处的临床前证据,许多研究人员认识到这些途径作为药物的潜力。因此,越来越多的 sirtuin 和 NAD + 促进药物的人体试验,其中一些在心血管和新陈代谢疾病中显示出保护作用(表3)。

Drug 药物Effect 效果Study Population 研究人口References 参考资料
Resveratrol白藜芦醇No change in walking performance 步行性能没有变化Patients with peripheral artery disease 周边动脉阻塞性疾病患者203
↑ Vascular function, No change in glucose metabolism 血管功能↑ ,葡萄糖代谢无变化Glucose intolerant adults 葡萄糖不耐受的成年人204
↓ Systolic blood pressure ↑ Insulin sensitivity ↓收缩压↑胰岛素敏感性Healthy obese men 健康的肥胖男性205
No effect 没有效果Healthy nonobese men 健康的非肥胖男性206
↓ Body weight ↓ Fat mass ↓ Total insulin secretion 4. ↓体重↓脂肪团↓胰岛素分泌总量Metabolic syndrome patients 代谢症候群的病人207
↓ Insulin resistance ↓ Fasting glucose 正在节食的葡萄糖↓胰岛素抵抗Type 2 diabetes mellitus patients 2型糖尿病的病人208
↑ Endothelial function ↑ Diastolic function 内皮功能↑舒张功能Patients with coronary artery disease 冠状动脉疾病患者209
↓ Serum LDL ↓ Insulin resistance 4. 胰岛素抵抗NAFLD patients 非酒精性脂肪肝患者210
↓ Hepatic steatosis ↓ Inflammation 4. 肝脏↓脂肪变性炎症NAFLD patients 非酒精性脂肪肝患者211
SRT2104↓ Body weight Changes to glucose control 4. 体重对葡萄糖控制的改变Type 2 diabetes mellitus patients 2型糖尿病的病人212
↓ Serum LDL ↓ Serum TGs 公司名片↓血清低密度脂蛋白Healthy older volunteers 健康的老年志愿者213
↓ Serum LDL ↓ Serum TGs 公司名片↓血清低密度脂蛋白Healthy smokers 健康的吸烟者214
Niacin 烟酸↓ Dyslipidemia 4. ↓血脂异常Varied 各式各样200
NRPT 核糖核酸转移酶Safely tolerated 安全地容忍Healthy volunteers 健康的志愿者215
NR 天然橡胶Safely tolerated 安全地容忍Healthy volunteers 健康的志愿者216,217
↓ Blood pressure ↓ Arterial stiffening 的血压↓动脉硬化Healthy volunteers 健康的志愿者218
Underway, aim to improve astherosclerosis and heart failure 目的在于改善动脉粥样硬化和心力衰竭Varied 各式各样No. NCT02812238 编号 NCT02812238
No. NCT03423342 编号 NCT03423342
(Clinicaltrials.gov)
NMN 核磁共振成像Underway, aim to improve cardiometabolic outcomes 目前的目标是改善心血管代谢的结果Women 55+ with dyslipidemia 55岁以上血脂异常的女性No. NCT03151239 编号 NCT03151239
(Clinicaltrials.gov)
INO-1001Safely tolerated 安全地容忍Patients with myocardial infarction 心肌梗死患者219
LDL indicates low-density lipoprotein; NAD+, nicotinamide adenine dinucleotide; NAFLD, nonalcoholic fatty liver disease; NMN, nicotinamide mononucleotide; NR, nicotinamide riboside; NRPT, nicotinamide riboside and pterostilbene; STAC, sirtuin-activating compound; and TG, triglyceride.

低密度脂蛋白表示低密度脂蛋白; NAD + ,烟酰胺腺嘌呤二核苷酸; NAFLD,非酒精性脂肪性肝病; NMN,烟酰胺单核苷酸; NR,烟酰胺核苷; NRPT,烟酰胺核苷酸和蝶呤二苯乙烯; STAC,sirtuin-activating compound; 甘油三酯,甘油三酯。

Sirtuin-Activating Compounds


Sirtuin-Activating 化合物

There have been >20 clinical trials of resveratrol, including at least 6 investigating cardiovascular outcomes and 8 with primary metabolic outcomes, including diabetes mellitus.220 Clinical trials of resveratrol have been recently and thoroughly reviewed6,220,221 with most trials showing beneficial cardiovascular and metabolic effects of resveratrol.6,220,221 For example, administration of resveratrol to healthy obese men for 30 days improved insulin sensitivity and decreased systolic blood pressure205 while no effect was seen in healthy nonobese men.206 Resveratrol treatment in patients with metabolic syndrome resulted in reduced body weight, reduced fat mass, and decreased total insulin secretion,207 and patients with type 2 diabetes mellitus treated with resveratrol for 45 days had lower fasting glucose and decreased insulin resistance than controls.208 Resveratrol has also shown improvements in patients with coronary artery disease209 and nonalcoholic fatty liver disease.36,211 Not all studies, however, have seen improvements with resveratrol treatment.203,220,221 Resveratrol treatment in glucose intolerant patients for 6 weeks resulted in improved vascular function with no effect on glucose tolerance or insulin sensitivity,204 and resveratrol treatment in patients with peripheral artery diseases did not improve the primary outcome of walking performance.203 Potential differences in clinical trial design, such as drug formulation, dose, and timing, may explain these varied results.6

已经有超过20个白藜芦醇的临床试验,包括至少6个调查心血管结果和8个原发代谢结果,包括糖尿病。最近对220个白藜芦醇的临床试验进行了全面的回顾,6,220,221个试验表明白藜芦醇对心血管和代谢有益。6,220,221例如,给健康的肥胖男性服用白藜芦醇30天可以提高胰岛素敏感性,降低收缩压,而对健康的非肥胖男性则没有效果。206例白藜芦醇治疗代谢症候群患者导致体重减轻,脂肪减少,总胰岛素分泌减少,207例白藜芦醇治疗45天2型糖尿病患者的空腹血糖和胰岛素抵抗比对照组低。白藜芦醇在冠状动脉疾病和非酒精性脂肪肝患者中也有改善。36,211然而,并非所有的研究都发现白藜芦醇疗法有所改善。203,220,221白藜芦醇治疗葡萄糖不耐受患者6周,改善血管功能,对葡萄糖耐量或胰岛素敏感性无影响,204和白藜芦醇治疗周围动脉疾病患者没有改善步行能力的初步结果。临床试验设计中的潜在差异,例如药物配方、剂量和时间,可以解释这些不同的结果

Clinical trials of the STAC SRT2104 have shown beneficial serum lipid-lowering effects in patients. A trial in healthy older volunteers found that SRT2014 decreased serum total cholesterol, LDL, and TG levels with no change in glucose tolerance.213 SRT2104 also reduced LDL and TG levels in healthy smokers but had no effect on the vasculature.214 A small crossover trial of SRT2104 in patients with type 2 diabetes mellitus found that drug treatment was associated with weight loss, but there was little effect on endothelial function or serum lipid profiles, and there was a potentially adverse effect on glucose control.212 The authors suggest that this negative effect may be a result of acute rather than chronic exposure to SRT2104 and that long-term exposure may mimic what is seen in preclinical studies.212

STAC SRT2104的临床试验显示了对患者有益的降血脂作用。一项在健康老年志愿者中进行的试验发现,SRT2014降低了血清总胆固醇、低密度脂蛋白和甘油三酯水平,而葡萄糖耐量没有变化。213 SRT2104也降低了健康吸烟者的低密度脂蛋白和甘油三酯水平,但对血管系统没有影响。214 SRT2104的一个小型交叉试验在2型糖尿病患者中发现,药物治疗与体重减轻有关,但对内皮功能或血脂几乎没有影响,而且对葡萄糖控制有潜在的不利影响。212作者认为,这种负面影响可能是急性而非慢性接触 SRT2104的结果,长期接触可能与临床前研究中的情况相似。212

NAD+ Boosters

推进器

There have been a few clinical trials of NAD+ boosters in treating cardiovascular or metabolic diseases with more currently underway.6,44 Niacin has been used for many years for the treatment of hypercholesteremia and acts to decrease very-low-density lipoprotein TGs by suppressing lipolysis200 although this effect may be NAD+ independent.201The first study of NR pharmacokinetics in healthy volunteers demonstrated safety and efficacy of single doses of NR in boosting NAD+ levels.216 A second pharmacokinetic study investigated the effect of 8 days of increased dosing of NR in healthy volunteers and also found that NR was well-tolerated and increased circulating NAD+ levels.217 Recently, these safety and pharmacokinetic results were confirmed in a 6-week clinical trial of NR in healthy older adults, and secondary analyses suggest it also reduced blood pressure and arterial stiffness.218 A combination of NR and the polyphenol compound pterostilbene was also found to be tolerated without side effects in a recent phase I trial.215 There are many more trials investigating NR in cardiovascular outcomes, including heart failure and atherosclerosis, currently underway.6,44 The first human trials of NMN are also ongoing.222 Safety and pharmacokinetics of the PARP inhibitor INO-1001 were investigated in a small study of patients with myocardial infarction, and it was found to be effective and well tolerated.219

目前已经有一些治疗心血管或代谢性疾病的 NAD + 促进剂的临床试验,更多的正在进行中。6,44烟酸多年来一直用于治疗高胆固醇血症,并通过抑制脂多糖200来降低极低密度脂蛋白过氧化物酶,尽管这种作用可能与 NAD + 无关。201首次在健康志愿者中进行的 NR 药代动力学研究表明单剂量 NR 提高 NAD + 水平的安全性和有效性。216第二次药代动力学研究了增加 NR 剂量8天对健康志愿者的影响,并发现 NR 具有良好的耐受性和增加循环 NAD + 水平。217最近,这些安全性和药代动力学结果在6周的 NR 在健康老年人中的临床试验中得到证实,二次分析表明,NR 还能降低血压和动脉僵硬度。218在最近的一期试验中也发现 NR 和多酚化合物紫檀可耐受,无副作用。215目前正在进行更多的试验,研究 NR 对心血管结果的影响,包括心力衰竭和动脉粥样硬化。6,44 NMN 的首批人体试验也在进行中。222 PARP 抑制剂 INO-1001的安全性和药代动力学在一项针对心肌梗死患者的小型研究中进行了调查,发现其有效性和耐受性良好。219

The overall promising results of STACs and NAD+ boosters in cardiovascular and metabolic diseases will result in further clinical trials of these compounds over the next decade and beyond.

STACs 和 NAD + 助推剂在心血管和新陈代谢疾病中的总体有希望的结果将导致这些化合物在未来十年及更长时间内进行进一步的临床试验。

Conclusions

结论

This review has shown the clear role of sirtuins and NAD+ in a range of cardiovascular and metabolic diseases and identified exciting opportunities to boost NAD+ and sirtuin activity to treat or prevent these diseases. In particular, there is extensive preclinical, and recently clinical, evidence for increasing SIRT1 activity to target type 2 diabetes mellitus and dyslipidemia. In addition, there is promising preclinical evidence for increasing SIRT6 activity in insulin resistance, increasing SIRT3 activity to protect against age-related cardiac hypertrophy, and boosting NAD+ levels to promote angiogenesis and increase blood flow, which may translate into clinical studies in the near future.

这篇综述已经显示了 sirtuins 和 NAD + 在一系列心血管和新陈代谢疾病中的明确作用,并且确定了刺激提高 NAD + 和 sirtuin 活性以治疗或预防这些疾病的机会。特别是,有广泛的临床前和最近的临床证据表明,增加 SIRT1活性可以靶向2型糖尿病和血脂异常。此外,有充分的临床前证据表明,增加 SIRT6在胰岛素抵抗中的活性,增加 SIRT3活性以防止与年龄相关的心肌肥大,提高 NAD + 水平以促进血管生成和增加血流量,这可能在不久的将来转化为临床研究。

There are still many questions that remain unanswered, however, and more research to be done. There is little known about sex differences in the roles of NAD+ and sirtuins in cardiovascular and metabolic diseases, and most preclinical studies have only been completed in males. Given the important sex differences in the cardiovascular system with aging223,224 and sex differences in response to longevity interventions,225 this area warrants further research. In addition, more research is needed on unraveling the role of each of the sirtuins in these age-related diseases, especially SIRT2, 4, 5, and 7, where little is currently known. The potentially divergent roles of different sirtuins in these diseases are not well understood, especially the possible detrimental roles of SIRT2 in IR injury and SIRT4 in hypertrophy. More research could improve understanding of how STACs may act differently on different sirtuins. Moreover, future studies should provide a better understanding of the effect of nutritional status on the role of sirtuins in glucose and insulin regulation and in dyslipidemia to optimize the use of sirtuin-modulating therapies in these conditions. In addition, there is still much to learn about the basic physiology and pharmacology of the NAD+-boosting drugs, such as their cellular transport, metabolism, and dosing before they can be widely used clinically. Although not discussed in this review, there is also the potential that diets that improve cardiovascular or metabolic outcomes226,227 may modulate NAD+ levels and increase sirtuin activity. For example, it has been suggested that increased NAD+ may be a significant mechanism contributing to the benefits of a high ketone diet.228

然而,仍然有许多问题没有得到解答,还有更多的研究要做。关于 NAD + 和去乙酰化酶在心血管和代谢疾病中的作用的性别差异知之甚少,大多数临床前研究只在男性中完成。考虑到心血管系统重要的性别差异与年龄的关系以及长寿干预的性别差异,这一领域需要进一步的研究。此外,还需要更多的研究来阐明每一种去乙酰化酶在这些与年龄相关的疾病中的作用,特别是 SIRT2、4、5和7,目前对它们知之甚少。不同去乙酰化酶在这些疾病中的潜在不同作用还没有得到很好的理解,特别是 SIRT2在 IR 损伤和 SIRT4在肥大中可能的有害作用。更多的研究可以提高人们对于 STACs 在不同去乙酰化酶上的不同反应的理解。此外,未来的研究应该提供一个更好的了解影响的营养状况的 sirtuin 在葡萄糖和胰岛素调节和血脂异常的作用,以优化使用 sirtuin 调节治疗这些条件。此外,还有许多关于 NAD + 促进药物的基本生理学和药理学的学习,例如他们的细胞转运,代谢和剂量之前,他们可以被广泛应用于临床。虽然在这篇综述中没有讨论,但是也有可能是饮食改善心血管或代谢结果226,227可能调节 NAD + 水平和增加 sirtuin 活性。例如,有人认为增加 NAD + 可能是一个重要的机制,有助于高酮饮食的好处

In conclusion, there is clear preclinical evidence for NAD+-boosting and sirtuin-activating therapies in treating and preventing age-related cardiovascular and metabolic diseases, which are resulting in growing translation of these promising interventions into clinical trials.

总之,有明确的临床前证据表明 NAD + 促进和去乙酰化酶激活疗法在治疗和预防与年龄有关的心血管和代谢疾病方面发挥作用,这使得这些有前途的干预措施越来越多地转化为临床试验。

Nonstandard Abbreviations and Acronyms

非标准缩写和首字母缩略词

ApoE 载脂蛋白 eapolipoprotein EE型载脂蛋白质
HFD 手足口病high-fat diet高脂饮食
IR 红外线ischemia-reperfusion缺血再灌注
LDL 低密度脂蛋白low-density lipoprotein低密度脂蛋白
NAD 美国国家广播公司+nicotinamide adenine dinucleotide烟酰胺腺嘌呤二核苷酸
NAMPT 国家动物保护行动计划nicotinamide phosphoribosyltransferase烟酰胺磷酸核糖基转移酶
NMN 核磁共振成像nicotinamide mononucleotide烟酰胺单核苷酸
NO 没有nitric oxide一氧化氮
NR 天然橡胶nicotinamide riboside烟酰胺核糖苷
PARP1poly ADP-ribose polymerase 1聚腺苷二磷酸核糖聚合酶1
SIR2 2silent information regulator 2无声信息调节器2号
STACs 美国国家科学院sirtuin-activating compounds去乙酰化酶激活化合物
TAC 交通谘询委员会transverse aortic constriction主动脉横缩
TG 甘油三酯triglyceride甘油三酯

Sources of Funding

资金来源

This work was supported by the Glenn Foundation for Medical Research and grants from the National Institutes of Health (RO1 AG028730 and RO1 DK100263). A.E.K. is supported by an NHMRC CJ Martin biomedical fellowship (GNT1122542).

这项研究得到了格伦医学研究基金会的支持,以及美国国立卫生研究院科学基金会的资助(RO1 AG028730和 RO1 DK100263)。A.e.k. 得到了美国国家卫生研究院马丁中心生物医学研究基金(GNT1122542)的支持。

Disclosures

披露

D.A. Sinclair is a consultant and inventor on patents licensed to Cohbar, Caudalie, Metro International Biotech, Jumpstart Fertility, Life Biosciences, and Liberty Biosecurity, and D.A. Sinclair is a consultant to EdenRoc Sciences, Senolytic Therapeutics, Spotlight Biosciences, and Continuum Biosciences. The other author reports no conflicts.

是获得 Cohbar、 Caudalie、都市日报生物技术、 Jumpstart 生育、生命生物科学和 Liberty Biosecurity 许可的专利顾问和发明家,而 d.a. Sinclair 是 EdenRoc Sciences、 Senolytic Therapeutics、 Spotlight Biosciences 和 Continuum Biosciences 的顾问。另一位作者报告说没有冲突。

Footnotes

脚注

Correspondence to Alice Kane, PhD, Department of Genetics, Harvard Medical School, 77 Ave Louis Pasteur, Boston MA 02115. Email 致 Alice Kane 博士,哈佛医学院遗传学系,77 Ave Louis Pasteur,Boston MA 02115. Emailalice_kane@hms. Alice kane@hmsharvard. 哈佛edu 教育

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