Abstract 012: Involvement of Drp1, A Mitochondrial Fission Inducer, in Angiotensin Ii-induced Hypertensive Vascular Remodeling in vitro and in vivo

Mitochondrial dysfunction has been implicated in various types of cardiovascular diseases which may involve overload and de-compensation in mitochondrial quality/quantity control. However, limited mechanistic insight is available regarding the contribution and mechanism of mitochondrial quality control in hypertension. In the present study, we tested our hypothesis that enhancement of mitochondrial fission via Drp1 activation in vascular smooth muscle cells (VSMCs) is involved in hypertensive vascular remodeling. Rat aortic VSMCs pretreated with adenovirus encoding Drp1 siRNA (Ad-siDrp1) or control non-silencing RNA (100 moi) were stimulated with 100 nM angiotensin II (AngII) up to 72 h. 8 week old male C57/BL6 mice were infused with (1000 ng/kg/min) for 2 weeks with or without treatment of Drp1 inhibitor mdivi1 (25 mg/kg ip every other day). In VSMCs, AngII induced transient mitochondrial fission (max at 2-4 h assessed by mito-tracker staining) associated with Drp1 phosphorylation at Ser616 (10-30 min). Pretreatment of ad-siDrp1 (100 moi) or mdivi1 (5 μM) attenuated AngII-induced mitochondrial fission. Ad-siDrp1 or mdivi1 also attenuated AngII-induced enhancements of mitochondrial reactive oxygen species (ROS) generation, total cell protein, cell volume and extracellular collagen content. In mice, mdivi1 significantly suppressed vascular hypertrophy and perivascular fibrosis induced by AngII in aorta, heart and kidney. mdivi1 also inhibited AngII-induced left ventricular hypertrophy assessed by heart weight body weight ratio (mg/g: 7.8±0.9 vs 6.3±0.2 p