Protective effects of sirtuins in cardiovascular diseases: from bench to bedside

Abstract

Sirtuins (Sirt1-Sirt7) comprise a family of nicotinamide adenine dinucleotide (NAD(+))-dependent enzymes. While deacetylation reflects their main task, some of them have deacylase, adenosine diphosphate-ribosylase, demalonylase, glutarylase, and desuccinylase properties. Activated upon caloric restriction and exercise, they control critical cellular processes in the nucleus, cytoplasm, and mitochondria to maintain metabolic homeostasis, reduce cellular damage and dampen inflammation-all of which serve to protect against a variety of age-related diseases, including cardiovascular pathologies. This review focuses on the cardiovascular effects of Sirt1, Sirt3, Sirt6, and Sirt7. Most is known about Sirt1. This deacetylase protects from endothelial dysfunction, atherothrombosis, diet-induced obesity, type 2 diabetes, liver steatosis, and myocardial infarction. Sirt3 provides beneficial effects in the context of left ventricular hypertrophy, cardiomyopathy, oxidative stress, metabolic homeostasis, and dyslipidaemia. Sirt6 is implicated in ameliorating dyslipidaemia, cellular senescence, and left ventricular hypertrophy. Sirt7 plays a role in lipid metabolism and cardiomyopathies. Most of these data were derived from experimental findings in genetically modified mice, where NFκB, Pcsk9, low-density lipoprotein-receptor, PPARγ, superoxide dismutase 2, poly[adenosine diphosphate-ribose] polymerase 1, and endothelial nitric oxide synthase were identified among others as crucial molecular targets and/or partners of sirtuins. Of note, there is translational evidence for a role of sirtuins in patients with endothelial dysfunction, type 1 or type 2 diabetes and longevity. Given the availability of specific Sirt1 activators or pan-sirtuin activators that boost levels of the sirtuin cofactor NAD⁺, we anticipate that this field will move quickly from bench to bedside.

Keywords: Aging; Cardiovascular; Metabolism; Sirtuins; Translational.

Figure 1

Specific and unspecific sirtuin activation. Caloric restriction, exercise, and increased activity of 5′-adenosine monophosphate activated protein kinase drive mitochondrial metabolism and expression of nicotinamide phosphoribosyltransferase. Consecutive synthesis of nicotinamide adenine diphosphate activates sirtuins. Another route of sirtuin activation is increased nicotinamide adenine diphosphate biosynthesis via supplementation of nicotinamide adenine diphosphate precursors such as nicotinic acid, nicotinamide, nicotinamide mononucleotide, and nicotinamide riboside or through inhibition of nicotinamide adenine dinucleotide-consuming activities, such as poly-adenosine diphosphate-ribose-polymerases or CD38. Sirt1-activating compounds may mimic the effects of Sirt1. Stimulation of Sirt1 activity by these distinct pathways improves the capacity of the cells/organism for metabolic adaptation and/or cardiovascular protection.

Figure 2

Cardiovascular effects of Sirt1. Within the nucleus Sirt1 interacts with diverse transcription factors, inhibiting NFκB signalling, and consecutive pro-inflammatory cytokine expression, e.g. vascular cell adhesion molecule 1 as well as expression of the reverse cholesterol transporter LXR. Moreover, Sirt1 reduces plasma Pcsk9 levels, thereby increasing hepatic low-density lipoprotein-cholesterol receptor density and thus decreasing plasma low-density lipoprotein-cholesterol levels. Along with activation of endothelial nitric oxide synthase, these effects improve endothelial dysfunction and decrease atherosclerosis. In addition, Sirt1 deacetylates NFκB and inhibits tissue factor activity and thereby slows arterial thrombus formation. Sirt1-mediated tissue factor inhibition may further follow activation of peroxisome proliferator-activated receptor delta and Cox2-derived prostaglandin synthesis.

Figure 3

Cardiovascular effects of Sirt3. Mitochondrial Sirt3 drives the tricarboxylic acid cycle, β-oxidation, and oxidative phosphorylation, thus maintaining metabolic homeostasis and preventing the development of risk factors associated with the metabolic syndrome. Deacetylation and consecutive activation of superoxide dismutase 2 mediates antioxidative protection, diminishes cardiac hypertrophy, and may improve endothelial dysfunction. Activation of the transcription factors NFATc2, STAT3, and HIF1α prevent the development of pulmonary hypertension.

Figure 4

Cardiovascular effects of Sirt6. Nuclear Sirt6-induced inhibition of insulin-like growth factor signalling prevents cardiac hypertrophy. Moreover, sirtuin 6-mediated reduction of plasma Pcsk9 levels increases hepatic low-density lipoprotein-receptor density and decreases plasma low-density lipoprotein-cholesterol levels. Poly[adenosine diphosphate-ribose] polymerase 1 activation halts reactive oxygen species-mediated DNA damage. Moreover, physical interaction of Sirt6 with the NFκB subunits RelA and p65 prevents their translocation to the nucleus and inhibits pro-inflammatory NFκB-signalling, thereby potentially protecting from endothelial dysfunction.

Figure 5

Cardiovascular effects of Sirt7. Nuclear Sirt7 deacetylates distinct lysine residues located in the hetero- and homodimerization domains of GA-binding protein (GABP)β1, a master regulator of nuclear-encoded mitochondrial genes. Along these lines, Sirt7 improves mitochondrial function in numerous tissues including cardiac and skeletal muscle where it protects from cardiomyopathy, lowers lactate levels, and improves exercise performance, respectively. Moreover, Sirt7 protects from hepatic micro-vesicular steatosis.