Mitochondrial Deacetylase Sirt3 as a New Target in Cardiovascular Diseases

Abstract

Multiple risk factors such as aging, vascular dysfunction, metabolic disorders and hypertension contribute to the pathogenesis of heart failure. The convergent mechanism that may underlie the interplay of these major risk factors is not clear but may provide novel strategies for treatment. Clinical studies show that Sirtuin 3 (Sirt3) expression declines by 40% by age 65 and sedentary lifestyle paralleling the increased incidence of cardiovascular diseases and heart failure while aerobic exercise increases Sirt3 expression and attenuates age‐dependent Sirt3 decline. Meanwhile, the pathophysiological role of Sirt3 depletion is not clear. Mitochondrial deacetylase Sirt3 is critical in regulation of mitochondrial metabolism and it activates a key antioxidant enzyme, superoxide dismutase 2 by deacetylation of specific lysine residues. We hypothesized that Sirt3 plays critical role in vascular dysfunction and hypertension. To test this hypothesis, we have developed new tamoxifen‐inducible endothelium specific Sirt3 knockout (EcSirt3KO), endothelial Sirt3 overexpressing (EcSirt3OX), smooth muscle Sirt3 knockout (SmcSirt3KO), smooth muscle Sirt3 overexpressing (SmcSirt3OX) and global Sirt3 overexpressing (Sirt3OX) mice on C57Bl/6J background, and examined the effect of Sirt3 expression on vascular dysfunction and angiotensin II‐induced hypertension. Sirt3 depletion in EcSirt3KO and SmcSirt3KO mice raises basal vascular permeability in the heart by 2‐fold, reduces endothelial NO, increases blood pressure and accelerates vascular aging compared with wild‐type mice. Angiotensin II infusion in EcSirt3KO and SmcSirt3KO mice caused vascular hyperpermeability, increased vascular hypertrophy, exacerbated endothelial dysfunction and hypertension. Meanwhile, Sirt3 overexpression attenuates vascular aging, normalizes vascular permeability, diminishes vascular inflammation, inhibits vascular oxidative stress, preserves endothelial‐dependent relaxation, reduces vascular hypertrophy and attenuates hypertension in Sham and angiotensin II‐infused EcSirt3OX and SmcSirt3OX mice compared with the wild‐type littermates. We suggest that Sirt3 is central in redox and metabolic regulations of smooth muscle and endothelial cells. As vascular permeability increases, the access of cytokines, inflammatory cells and LDL to tissue is greater contributing to cardiac inflammation, altered tissue remodeling, hypertrophy and dysfunction. Our data support a therapeutic potential of targeting Sirt3 in cardiovascular dysfunction and hypertension which can improve treatment of the heart failure.Support or Funding InformationThis work was supported by funding from National Institute of Health (NHLBI 1R01HL124116) and American Heart Association (16GRNT31230017).This abstract is from the Experimental Biology 2019 Meeting. There is no full text article associated with this abstract published in The FASEB Journal.