December 21, 2007
View Full PaperMolecular Mechanisms of Angiotensin II–Mediated Mitochondrial Dysfunction
Key Result
Angiotensin II induces mitochondrial dysfunction via a protein kinase C-dependent pathway by activating endothelial cell NADPH oxidase and forming peroxynitrite.
Structured PICO
Does Angiotensin II induce mitochondrial dysfunction and decrease endothelial NO bioavailability in bovine aortic endothelial cells?
P
Population
Isolated mitochondria and intact bovine aortic endothelial cells
I
Intervention
Angiotensin II
C
Comparator
Control or preincubation with various inhibitors (apocynin, uric acid, chelerythrine, N(G)-nitro-L-arginine methyl ester, 5-hydroxydecanoate, glibenclamide, or small interfering RNA for p22(phox))
O
Outcome
Mitochondrial ROS (H2O2 production), mitochondrial respiration, membrane potential, glutathione, and endothelial NO bioavailabilitysurrogate
Angiotensin II induces mitochondrial dysfunction via a protein kinase C-dependent pathway that activates NADPH oxidase, leading to decreased endothelial nitric oxide bioavailability.
Abstract
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), N(G)-nitro-L-arginine methyl ester (nitric oxide synthase inhibitor), 5-hydroxydecanoate (mitochondrial ATP-sensitive potassium channels inhibitor), or glibenclamide. Depletion of p22(phox) 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.
Cite This Study
Doughan et al. (Fri,) conducted a other in Mitochondrial dysfunction. Angiotensin II was evaluated on Mitochondrial H2O2 production, respiration, membrane potential, glutathione, and endothelial NO bioavailability. Angiotensin II induces mitochondrial dysfunction via a protein kinase C-dependent pathway by activating endothelial cell NADPH oxidase and forming peroxynitrite.