Nox2-Induced Production of Mitochondrial Superoxide in Angiotensin II-Mediated Endothelial Oxidative Stress and Hypertension

• DOI: 10.1089/ars.2012.4918
• Publication Date: 2013-09-22T14:31:20Z
• Authors: Sergey I. Dikalov; Rafal R. Nazarewicz; Alfiya Bikineyeva; Lula Hilenski; Bernard Lassègue; Kathy K. Griendling; David G. Harrison; Anna E. Dikalova
• Keywords: Mitochondrial ROS; Apocynin; NOX4

Angiotensin II (AngII)-induced superoxide (O2(•-)) production by the NADPH oxidases and mitochondria has been implicated in pathogenesis of endothelial dysfunction hypertension. In this work, we investigated specific molecular mechanisms responsible for stimulation mitochondrial O2(•-) its downstream targets using cultured human aortic cells a mouse model AngII-induced hypertension.Western blot analysis showed that Nox2 Nox4 were present cytoplasm but not mitochondria. Depletion Nox2, Nox1, Nox4, or Nox5, siRNA inhibits both cytoplasm. depletion gp91phox knockout mice inhibited cellular attenuated Inhibition reverse electron transfer with malonate, malate, rotenone cytoplasmic production. ATP-sensitive potassium channel (mitoK(+)ATP) 5-hydroxydecanoic acid PKCɛ peptide antagonist (EAVSLKPT) reduced H2O2 isolated diminished O2(•-). The mitoK(+)ATP agonist diazoxide increased O2(•-), c-Src phosphorylation suggesting feed-forward regulation reactive oxygen species (ROS). Treatment AngII-infused malate blood pressure enhanced antihypertensive effect mitoTEMPO. Mitochondria-targeted scavenger mitoEbselen redox-dependent H2O2, hypertensive mice.These studies show stimulates ROS activating may represent new pharmacological treatment