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Am J Physiol Heart Circ Physiol 292: H1664-H1674, 2007. First published January 12, 2007; doi:10.1152/ajpheart.01138.2006
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Oxygen Sensing: Life and Death of a Cell

NADPH oxidase modulates myocardial Akt, ERK1/2 activation, and angiogenesis after hypoxia-reoxygenation

¹Department of Pediatrics, Divisions of Neonatology, and ²Department of Pathology and Medicine, Vanderbilt University Medical Center, Nashville, Tennessee

Submitted 16 October 2006 ; accepted in final form 10 January 2007

Recent studies have demonstrated that reactive oxygen species (ROS) mediate myocardial ischemia-reperfusion (I/R) and angiogenesis via the mitogen-activated protein kinases and the serine-threonine kinase Akt/protein kinase B pathways. NADPH oxidases are major sources of ROS in endothelial cells and cardiomyocytes. In the present study, we investigated the role of NADPH oxidase-derived ROS in hypoxia-reoxygenation (H/R)-induced Akt and ERK1/2 activation and angiogenesis using porcine coronary artery endothelial cells (PCAECs) and a mouse myocardial I/R model. Our data demonstrate that exposure of PCAECs to hypoxia for 2 h followed by 1 h of reoxygenation significantly increased ROS formation. Pretreatment with the NADPH oxidase inhibitors, diphenyleneiodonium (DPI, 10 µM) and apocynin (Apo, 200 and 600 µM), significantly attenuated H/R-induced ROS formation. Furthermore, exposure of PCAECs to H/R caused a significant increase in Akt and ERK1/2 activation. Exposure of PCAEC spheroids and mouse aortic rings to H/R significantly increased endothelial spheroid sprouting and vessel outgrowth, whereas pharmacological inhibition of NADPH oxidase or genetic deletion of the NADPH oxidase subunit, p47^phox (p47^phox–/–), significantly suppressed these changes. With the use of a mouse I/R model, our data further show that the increases in myocardial Akt and ERK1/2 activation and vascular endothelial growth factor (VEGF) expression were markedly blunted in the p47^phox–/– mouse subjected to myocardial I/R compared with the wild-type mouse. Our findings underscore the important role of NADPH oxidase and its subunit p47^phox in modulating Akt and ERK1/2 activation, angiogenic growth factor expression, and angiogenesis in myocardium undergoing I/R.

mouse model of ischemia-reperfusion; reduced nicotinamide adenine dinucleotide phosphate oxidase-derived reactive oxygen species; serine-threonine kinase Akt/protein kinase B; extracellular signal-regulated kinase; p47^phox mouse

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