Journal of molecular histologySep 10, 2026

Cell-level sirtuin signaling networks as key controllers of heart function and repair

Longevity & Aging Weekly Brief ↗PubMed ↗DOI ↗

Updated Sep 11, 2026

Abstract

Sirtuins are a family of enzymes that regulate key biological processes and may play essential roles in cardiovascular health.

Sirtuins function as NAD⁺-dependent deacylases involved in metabolism, inflammation, and stress responses.
Overexpression of Sir2 in yeast extends lifespan, while its deletion shortens it, indicating its role in longevity.
In mammals, SIRT1-7 serve as critical regulators across various tissues, influencing genomic stability and cardiovascular health.
SIRT4 and SIRT5 have distinct activities, with SIRT4 exhibiting mono-ADP-ribosylation and SIRT5 targeting negatively charged acyl groups.
Sirtuins may mitigate cardiovascular remodeling, atherosclerosis, and heart failure, particularly through regulating macrophage polarization and vascular inflammation.
Caloric restriction and pharmacological activators are proposed as potential therapeutic strategies for enhancing sirtuin function in cardiovascular disease.

Simplified

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.

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Cell-level sirtuin signaling networks as key controllers of heart function and repair

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