Role of Mitochondrial Oxidative Stress in Endothelial Dysfunction and Hypertension

Abstract

Oxidative stress is strongly implicated in the pathogenesis of hypertension; however, the role of mitochondrial oxidative stress is not clear. We have investigated the role of mitochondria in endothelial dysfunction and hypetention using cultured bovine endothelial cells (BAECs) and mice infused with angiotensin II (AngII) or DOCA-salt mice. Production of O2▸ was measured by dihydroethidium and HPLC. Nitric oxide and H2O2 were detected by ESR. Stimulation of BAECs with AngII significantly increased mitochondrial H2O2. MitoTEMPO blocked AngII-induced oxidative stress and restored NO▸ production in BAECs and mouse aorta. Supplementation of BAECs with malonate, inhibitor of complex II, or rotenone, inhibitor of reverse electron transport, abolished AngII induced oxidative stress and decreased the activity of NADPH oxidases. Infusion of with mitoTEMPO significantly attenuated the increase in the blood pressure (Fig.1), while mitoTEMPO treatment of hypertensive mice decreased the blood presure by 20-30 mm Hg both in AngII-infused and DOCA-salt mice. Meanwhile, non-targeted antioxidant TEMPOL was not effective. We suggest that AngII stimulates NADPH oxidase, which induces mitochondrial oxidative stress that in turn provides redox dependent feed forward stimulation of NADPH oxidase. This vicious cycle can be terminated at the mitochondrial site by mitoTEMPO. Indeed, mitoTEMPO inhibited vascular oxidative stress and reduced blood pressure. Figure 1. Attenuation of hypertensive effect of Ang II (0.7mg/kg/day) in C57Blk/6 mice with mitoTEMPO or TEMPOL (286 nmol/kg/day).Open in figure viewerPowerPoint