Subcellular sirtuin signaling networks: pivotal regulators of cardiovascular homeostasis and remodeling

Sirtuins represent a family of highly conserved enzymes, initially identified as Silent Information Regulator 2 (Sir2) in yeast, where they serve as fundamental determinants of longevity. Overexpression of Sir2 in yeast significantly extends lifespan, while its deletion leads to shortened longevity. In mammals, sirtuins (SIRT1-7) represent a conserved family of NAD⁺-dependent deacylases with diverse catalytic activities. While most members primarily function as deacetylases, SIRT4 exhibits mono-ADP-ribosylation activity, and SIRT5 uniquely targets negatively charged acyl groups, including lysine succinylation, malonylation, and glutarylation. These enzymes act as critical intracellular sensors and regulators widely distributed across diverse tissues. By targeting a broad array of protein substrates, they regulate core biological processes-including genomic stability, metabolism, inflammation, and stress responses. As cardiovascular diseases (CVDs) remain the primary cause of global mortality, driven by complex pathologies such as chronic inflammation and metabolic dysregulation, the sirtuin network has emerged as an indispensable regulator of cardiovascular health. This review systematically elucidates the pivotal roles of sirtuins in cardiovascular homeostasis. We provide an in-depth, subcellular perspective on how nuclear, cytoplasmic, and mitochondrial sirtuins synergistically protect against cardiovascular remodeling, atherosclerosis (AS), and heart failure (HF). Particular emphasis is placed on the molecular mechanisms modulating macrophage polarization and the mitigation of vascular inflammation via the NF-κB signaling pathway. Furthermore, we assess the therapeutic promise of caloric restriction (CR) and pharmacological activators, incorporating recent human clinical evidence. We propose a framework matching sirtuin-based interventions to disease tempo, advocating isoform and compartment-specific strategies for acute and chronic CVDs.