**Background:** Cardiovascular diseases (CVD) remain the most common cause of death globally, contributing to 17.5 million deaths annually (approximately 31% of global mortality). Atherosclerosis, the primary cause of CVD, is characterized by luminal occlusion of arteries due to extracellular fat deposition and thrombus formation, leading to atheromatous plaques. Plaques are classified as stable (non-vulnerable) or unstable (vulnerable), with approximately 75% of all coronary events such as strokes and myocardial infarction stemming from plaque rupture and erosion. Key factors mediating plaque vulnerability include endothelial cell dysfunction, reactive oxidative species (ROS), macrophage and lymphocyte infiltration, LDL levels, and chronic inflammation. Sirtuins (SIRTs), a family of NAD+-dependent deacetylases (SIRT1-7), are involved in sustaining genome integrity, DNA repair, modulating oxidative stress, aging, inflammation, and energy metabolism. This review critically discusses the role of SIRTs in plaque progression and vulnerability and the possibility of targeting SIRTs to attenuate plaque rupture.
**Methods:** This is a narrative review synthesizing existing literature on the molecular mechanisms linking sirtuins to atherosclerosis and plaque vulnerability. The authors discuss evidence from in vitro studies, animal models (primarily ApoE−/− and LDLr−/− mice), and human case-control studies. They examine the roles of individual sirtuins (SIRT1, SIRT2, SIRT3, SIRT6, SIRT7) in inflammatory signaling, oxidative stress, hypoxia, and cellular senescence as they relate to plaque stability. A summary table (Table 1) catalogs key studies investigating the role of sirtuins in atherosclerosis, including experimental models and outcomes.
**Key Results:** The review identifies several critical molecular pathways: (1) SIRT1 suppresses NF-κB, COX-2, and iNOS production by deacetylating the p65 subunit of the NF-κB complex, and also activates AMPK, PPARα, and PGC-1α to inhibit NF-κB signaling. (2) SIRT2 deacetylates the p65 subunit of NF-κB and RIP-1, and in LDLr−/− mice, SIRT2 significantly decreased plaque area, macrophage infiltration, and iNOS expression while increasing ARG-1 levels, enhancing plaque stability by attenuating macrophage polarization toward the M1 phenotype. (3) SIRT3, a stress-responsive mitochondrial deacetylase, reduces ROS through activation of FOXO3a and expression of ROS-scavenging enzymes; SIRT3 knockout cells have higher levels of superoxide radicals and are more prone to genetic vulnerability. (4) SIRT6 interacts with p65/RelA bound to the NF-κB promoter region to repress transcription; SIRT6 expression was significantly higher in non-diabetics compared to diabetics, and SIRT6 overexpression decreased proliferation of atherogenic genes such as TNFSF4. (5) SIRT1 increases during hypoxia, with HIF1α shown to increase gene expression of SIRT1, though the reciprocal relationship remains unclear. (6) Genetic polymorphisms in SIRT3 and SIRT6 were found in higher correlation with patients with coronary artery disease. (7) SIRT1 is negatively correlated to cholesterol content and risk of CVD in human studies. (8) SIRT7 is a dynamic nuclear regulator of mitochondrial function through its impact on GABPβ1 function.
**Clinical Implications:** The authors argue that sirtuins represent promising therapeutic targets for attenuating plaque vulnerability and atherosclerosis progression. Sirtuin Activators (STACs) may inhibit senescent cell-mediated secretion of chemokines, particularly through overexpression of SIRT1, which inhibits p53/p21 signaling and maintains telomere health. SIRT6 overexpression may impair monocyte adhesion to endothelial cells by decreasing TNFSF4. The concurrent prevalence of diabetes and CVD highlights the importance of sirtuin-mediated regulation of calcification, inflammation, and infiltration. The COVID-19 pandemic has further underscored this relevance, as SARS-CoV-2 interaction with ACE2 receptors reduces ACE2 levels, preventing degradation of atherosclerotic AngII, while sirtuins may downregulate AngII and promote anti-oxidant activity. The authors conclude that targeting sirtuins through sirtuin activators and modulators can potentially yield significant attenuation of plaque formation and vulnerability, though they note that the literature on the role of sirtuins in regulating vascular health remains limited and further investigation is needed.