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1 Pediatrics, Vanderbilt University Medical Center, Nashville, Tennessee, United States
2 Pathology, Vanderbilt University Medical Center, Nashville, Tennessee, United States
3 Division of Neonatology, Vanderbilt University, Nashville, Tennessee, United States
* To whom correspondence should be addressed. E-mail: jian-xiong.chen{at}vanderbilt.edu.
Recent studies have demonstrated that reactive oxygen species (ROS) mediate myocardial ischemia/reperfusion (I/R) and angiogenesis via the mitogen-activated protein kinases (MAPKs) and the serine-threonine kinase Akt/protein kinase B (PKB) 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 ischemia/reperfusion (I/R) model. Our data demonstrate that exposure of PCAECs to hypoxia for two hours followed by one hour of reoxygenation significantly increased ROS formation. Pretreatment with the NADPH oxidase inhibitors, diphenylene iodinium (DPI, 10 µM) and apocynin (Apo, 200 and 600µM), significantly attenuated H/R-induced ROS formation. Further, exposure of PCAECs to H/R caused a significant increase in Akt and ERK1/2 activation. Exposure of PCAECs spheroids and mouse aortic rings to H/R significantly increased endothelial spheroids sprouting and vessel outgrowth, whereas pharmacological inhibition of NADPH oxidase or genetic deletion of the NADPH oxidase subunit, p47phox, (p47phox-/-) significantly suppressed these changes. Using 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 p47phox-/- mouse subjected to myocardial I/R, compared with the wild type mouse. Our findings underscore the important role of NADPH oxidase and its subunit, p47phox, in modulating Akt and ERK1/2 activation, angiogenic growth factor expression and angiogenesis in myocardium undergoing ischemia/reperfusion.
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