The enigmatic role of SIRT2 in the cardiovascular system: Deciphering its protective and detrimental actions to unlock new avenues for therapeutic intervention

•Context-dependent protective and harmful effects of SIRT2 in various cardiovascular pathologies, including hypertrophy and vascular dysfunction.•SIRT2 is not solely a deacetylase but has diverse catalytic activities, each with important roles in cardiovascular health.•SIRT2 has knowledge gaps in its mechanisms of action in the cardiovascular system; the other Sirtuin isoforms do not.•Uniting our understanding of SIRT2′s context-dependent roles and unique catalytic activities will undermine its therapeutic potential.•To guide therapeutic interventions towards cardiovascular development, aging, and disease by filling research gaps on SIRT2 activities. 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.