Abstract 4878: Role of Mitochondrial Superoxide in Endothelial Dysfunction and Hypertension
Background. Superoxide (O2−•) production by vascular NADPH oxidase is strongly implicated in the pathogenesis of hypertension; however, the role of mitochondrial O2−• is not clear. In this work we have investigated the role of mitochondrial O2−• in endothelial dysfunction and hypertension in cultured human aortic endothelial cells and in hypertensive mice using mitochondria-targeted superoxide dismutase mimetic mitoTEMPO, depletion or overexpression of mitochondrial superoxide dismutase (SOD2).
Results. We found that supplementation of AngII-stimulated endothelial cells with mitoTEMPO decreased AngII-stimulated mitochondrial O2−•, inhibited production of cellular O2−•, restored nitric oxide (NO), attenuated c-Src activity and inhibited NADPH oxidase. SOD2 plasmid increased SOD activity in mitochondria but not in the cytoplasm, however, it inhibited cytoplasm NADPH oxidase and blocked AngII-induced cellular O2−•. SOD2 depletion with siRNA increased both basal and AngII-stimulated cellular O2−• due to higher NADPH oxidase activity while mitoTEMPO treatment mimicked SOD2 overexpression. Infusion of mitoTEMPO to AngII-treated mice attenuated AngII-induced hypertension. mito-TEMPO treatment after the onset of hypertension decreased blood pressure by 30 mm Hg both in AngII-infused and DOCA-salt mice (Table 1⇓). The antihypertensive effect of mitoTEMPO was accompanied by decreased vascular O2−•, increased vascular NO production and recovery of endothelial-dependent relaxation. Interestingly, mice transgenic for mitochondrial SOD2 demonstrated attenuated AngII-induced hypertension and vascular oxidative stress similar to mitoTEMPO supplementation (Table 1⇓).
Conclusion. Our data show that mitochondrial O2−• is important for regulation of vascular NADPH oxidase and it represents a novel therapeutic target to treat endothelial dysfunction and hypertension.
This research has received full or partial funding support from the American Heart Association, National Center.