Published online before print December 20, 2007, doi: 10.1161/CIRCRESAHA.107.162800
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© 2008 American Heart Association, Inc.
Integrative Physiology |
Molecular Mechanisms of Angiotensin II–Mediated Mitochondrial Dysfunction
Linking Mitochondrial Oxidative Damage and Vascular Endothelial Dysfunction
From the Division of Cardiology and Department of Medicine (A.K.D., D.G.H., S.I.D.), Emory University School of Medicine, Atlanta; and the Atlanta Veterans Administration Hospital (D.G.H.), Ga.
Correspondence to Sergey I. Dikalov, PhD, Emory University School of Medicine, Division of Cardiology, 1639 Pierce Dr, Suite 319 WMB, Atlanta, GA 30322. E-mail dikalov{at}emory.edu
Mitochondrial dysfunction is a prominent feature of most cardiovascular diseases. Angiotensin (Ang) II is an important stimulus for atherogenesis and hypertension; however, its effects on mitochondrial function remain unknown. We hypothesized that Ang II could induce mitochondrial oxidative damage that in turn might decrease endothelial nitric oxide (NO·) bioavailability and promote vascular oxidative stress. The effect of Ang II on mitochondrial ROS, mitochondrial respiration, membrane potential, glutathione, and endothelial NO· was studied in isolated mitochondria and intact bovine aortic endothelial cells using electron spin resonance, dihydroethidium high-performance liquid chromatography –based assay, Amplex Red and cationic dye fluorescence. Ang II significantly increased mitochondrial H2O2 production. This increase was blocked by preincubation of intact cells with apocynin (NADPH oxidase inhibitor), uric acid (scavenger of peroxynitrite), chelerythrine (protein kinase C inhibitor), NG-nitro-L-arginine methyl ester (nitric oxide synthase inhibitor), 5-hydroxydecanoate (mitochondrial ATP-sensitive potassium channels inhibitor), or glibenclamide. Depletion of p22phox subunit of NADPH oxidase with small interfering RNA also inhibited Ang II–mediated mitochondrial ROS production. Ang II depleted mitochondrial glutathione, increased state 4 and decreased state 3 respirations, and diminished mitochondrial respiratory control ratio. These responses were attenuated by apocynin, 5-hydroxydecanoate, and glibenclamide. In addition, 5-hydroxydecanoate prevented the Ang II–induced decrease in endothelial NO· and mitochondrial membrane potential. Therefore, Ang II induces mitochondrial dysfunction via a protein kinase C–dependent pathway by activating the endothelial cell NADPH oxidase and formation of peroxynitrite. Furthermore, mitochondrial dysfunction in response to Ang II modulates endothelial NO· and 
generation, which in turn has ramifications for development of endothelial dysfunction.
Key Words: mitochondria • angiotensin II • endothelial cells • oxidative stress
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