The Enigmatic Role of SIRT2 in the Cardiovascular System: Deciphering its Protective and Detrimental Actions to Unlock New Avenues for Therapeutic Intervention.

Cardiovascular diseases (CVDs) are leading causes of mortality throughout the world, and hence, there is a critical need to elucidate their molecular mechanisms. The Sirtuin (SIRT) family of NAD+-dependent enzymes has recently been shown to play a critical role in cardiovascular health and disease, and several SIRT isoforms, especially SIRT1 and SIRT3, have been amply investigated. However, the precise function of SIRT2 is only partially explored. Here, we review the current understanding of the involvement of SIRT2 in various cardiovascular pathologies, such as cardiac hypertrophy, ischemia-reperfusion injury, diabetic cardiomyopathy, and vascular dysfunction, with emphasis placed on the context-dependent protective or deleterious actions of SIRT2, including its wide array of catalytic activities which span beyond deacetylation. Furthermore, the review uncovers several unresolved research gaps for SIRT2 mechanisms by which SIRT2 modulates cardiac and vascular function during development and aging, thereby paving the way for the discovery of novel therapeutic targets as well as SIRT2-targeted interventions in the prevention and treatment of various cardiovascular diseases.