SIRT3 Attenuates Hypertensive Cardiac Remodeling By Promoting Angiogenesis

Aims:Emerging evidence indicates that impaired angiogenesis may contribute to hypertension-induced cardiac remodeling.The NAD-dependent deacetylase Sirtuin 3（SIRT3）has the potential to modulate angiogenesis,but this has not been confirmed.As such,the aim of this study was to examine the relationship between SIRT3-mediated angiogenesis and cardiac remodeling.Methods:8-week-old male SIRT3 knockout（KO）,endothelial cell-specific SIRT3 transgenic(SIRT3-Tg^EC)and age-matched wild-type（WT）mice were infused with AngⅡ（1.4μg/kg/min）or normal saline（NS）for 14 days.Weaning male Sprague-Dawley rats were fed with a standard chow diet（ND）or high-fat diet（HFD）for 8 weeks.Echocardiography was performed to assess cardiac function.Myocardial structure and function was verified by histochemistry and immunohistochemistry staining.Cardiac microvascular rarefaction was measured by Microfil perfusion.In vitro,cardiac microvascular endothelial cells（CMVECs）were treated with AngⅡof10^-6 mol/L for 12h.SIRT3 sh RNA and LV-SIRT3 virus were transfected into CMVECs to knock down or increase SIRT3 expression.The angiogenic capacity and ROS generation were detected and the expression of autophagy related proteins was analyzed by western blot.Results:After Ang II infusion,SIRT3 KO mice developed more severe capillary rarefaction and functional hypoxia in cardiac tissues as compared to WT mice.These events were concomitant with mitochondrial dysfunction and enhanced collagen-I and collagen-III expression,leading to cardiac fibrosis.Silencing SIRT3 facilitated Ang II-induced aberrant Pink/Parkin acetylation and impaired mitophagy,while excessive mitochondrial reactive oxygen species（ROS）generation limited glycolysis and angiogenic capacity in primary mouse cardiac microvascular endothelial cells（CMVECs）.Moreover,SIRT3 overexpression in CMVECs enhanced Pink/Parkin-mediated mitophagy,attenuated mitochondrial ROS generation,and restored vessel sprouting and tube formation.In parallel,endothelial cell-specific SIRT3 transgenic mice(SIRT3-Tg^EC)showed decreased fibrosis,as well as improved cardiac function and microvascular network,compared to WT mice with similar stimuli.Nebivolol attenuated obesity-induced cardiac hypertrophy and myocardial inflammation through upregulating SIRT3 expression.Conclusions:Collectively,these findings suggest that SIRT3 could promote angiogenesis and glycolysis through attenuating mitochondrial dysfunction caused by defective mitophagy.Nebivolol may act as a SIRT3 agonist for cardioprotective effects.