Sirtuin 1 in Endothelial Dysfunction and Cardiovascular Aging

Abstract

Sirtuin 1 (SIRT1) is a histone deacetylase belonging to the family of Sirtuins, a class of nicotinamide adenine dinucleotide (NAD+)-dependent enzymes with multiple metabolic functions. SIRT1 localizes in the nucleus and cytoplasm, and is implicated in the regulation of cell survival in response to several stimuli, including metabolic ones. The expression of SIRT1 is associated with lifespan and is reduced with aging both in animal models and in humans, where the lack of SIRT1 is regarded as a potential mediator of age-related cardiovascular diseases. In this review, we will summarize the extensive evidence linking SIRT1 functional and quantitative defects to cellular senescence and aging, with particular regard to their role in determining endothelial dysfunction and consequent cardiovascular diseases. Ultimately, we outline the translational perspectives for this topic, in order to highlight the missing evidence and the future research steps.

Keywords: aging–old age–seniors; atherosclerosis; cardiovascular disease; eNOS (endothelial nitric oxide synthase); endothelial (dys)function; inflammaging; sirtuin (SIRT1).

Figure 1

SIRT1 and endothelial dysfunction. Summary of molecular mechanisms (created with BioRender.com). ADMA, asymmetric dimethyl-arginine; APE1, apurinic/apyrimidinic endonuclease 1; eNOS, endothelial nitric oxide synthase; FOXO, forkhead box O class; γ-GCS, γ-glutamylcysteine synthetase; GST Ya, glutathione S-transferase Ya; HO 1, heme oxygenase 1; IFNγ, interferon γ; mTOR, mechanistic target of Rapamycin; NAD: nicotinamide adenine dinucleotide; NF-κB, nuclear factor kappa-light-chain-enhancer of activated B cells; Nrf2, nuclear factor erythroid 2—related factor 2; ROS, reactive oxygen species; SIRT1, Sirtuin 1; SOD2, superoxide dismutase 2.

Figure 2

Translational relevance of SIRT1. Summary of potential pharmacologic and non-pharmacologic interventions to increase SIRT1 activity (created with BioRender.com). eNOS, endothelial nitric oxide synthase; FOXO, forkhead box O class; NAD, nicotinamide adenine dinucleotide; NO, nitric oxide; SIRT1, Sirtuin 1; NF-κB, nuclear factor kappa-light-chain-enhancer of activated B cells.