Abstract
Introduction: Failure of several multi-center clinical trials using antioxidants to improve outcomes in patients with cardiovascular disease, and the recent findings showing paradoxical role for NADPH oxidase-derived reactive oxygen species (ROS) in endothelial function challenge a long-held notion that higher ROS levels are harmful for vascular function. Hypothesis: We examined the hypothesis that endothelium-specific conditional increase in NADPH oxidase-derived ROS will induce stress-signal-mediated activation of eNOS and thus improve coronary endothelial function. Methods: We have generated a novel binary (Tet-ON/OFF) conditional transgenic mouse (Tet-Nox2:VE-Cad-tTA) that induces endothelial cell (EC)-specific overexpression of Nox2/gp91 (NADPH oxidase) and 1.8±0.42-fold increase in EC-ROS upon tetracycline withdrawal (Tet-OFF). We examined the effects of increased ROS on EC signaling and coronary endothelial function using eight animals in each group (Tet-ON and Tet-OFF). Results: First, we demonstrate that endothelium-dependent coronary vasodilation was significantly improved in Tet-OFF Nox2 compared to Tet-ON (control) littermates. Using EC isolated from mouse heart (MHEC), we demonstrate that Nox2-derived ROS increased eNOS activation and nitric oxide (NO) synthesis through activation of the survival kinase AMPK. We also show that endothelium-dependent coronary vasodilation in Tet-OFF Nox2 animals was CaMKKβ-AMPK-dependent. Finally, we demonstrate that AMPK activation induced autophagy and thus, protected ECs from oxidant-induced cell death in these animals. Together, these results suggest that activation of AMPK plays an important role in EC survival and endothelial function during oxidative stress. Conclusion: These findings suggest that increased ROS levels, often associated with pathophysiological conditions, play a protective role in endothelial homeostasis by inducing AMPK-eNOS axis.
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