title: Oxidative stress improves coronary endothelial function through activation of the pro-survival kinase AMPK.
abstract: Age-associated decline in cardiovascular function is believed to occur from the deleterious effects of reactive oxygen species (ROS). However, failure of recent clinical trials using antioxidants in patients with cardiovascular disease, and the recent findings showing paradoxical role for NADPH oxidase-derived ROS in endothelial function challenge this long-held notion against ROS. Here, we examine the effects of endothelium-specific conditional increase in ROS on coronary endothelial function. 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 ROS effects on EC signaling and function. 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, we show that endogenous ROS increased eNOS activation and nitric oxide (NO) synthesis through activation of the survival kinase AMPK. Coronary vasodilation in Tet-OFF Nox2 animals was CaMKK?-AMPK-dependent. Finally, we demonstrate that AMPK activation induced autophagy and thus, protected ECs from oxidant-induced cell death. Together, these findings suggest that increased ROS levels, often associated with cardiovascular conditions in advanced age, play a protective role in endothelial homeostasis by inducing AMPK-eNOS axis.
authors.affiliation: Cardiovascular Research Center, Division of Cardiothoracic Surgery, Department of Surgery, Rhode Island Hospital, Providence, RI 02903, USA.
authors.forename: Ehtesham
authors.initials: E
authors.lastname: Shafique
authors.forename: Wing C
authors.initials: WC
authors.lastname: Choy
authors.forename: Yuhong
authors.initials: Y
authors.lastname: Liu
authors.forename: Jun
authors.initials: J
authors.lastname: Feng
authors.forename: Brenda
authors.initials: B
authors.lastname: Cordeiro
authors.forename: Arthur
authors.initials: A
authors.lastname: Lyra
authors.forename: Mohammed
authors.initials: M
authors.lastname: Arafah
authors.forename: Abdulmounem
authors.initials: A
authors.lastname: Yassin-Kassab
authors.forename: Arthus V D
authors.initials: AV
authors.lastname: Zanetti
authors.forename: Richard T
authors.initials: RT
authors.lastname: Clements
authors.forename: Cesario
authors.initials: C
authors.lastname: Bianchi
authors.forename: Laura E
authors.initials: LE
authors.lastname: Benjamin
authors.forename: Frank W
authors.initials: FW
authors.lastname: Sellke
authors.forename: Md Ruhul
authors.initials: MR
authors.lastname: Abid
mesh_terms: D000263:Adenylate Kinase / Q000235:genetics / Q000378:metabolism*; D000375:Aging / Q000502:physiology*; D000818:Animals; D001343:Autophagy; D002478:Cells, Cultured; D003331:Coronary Vessels / Q000502:physiology*; D042783:Endothelial Cells / Q000378:metabolism; D004730:Endothelium, Vascular / Q000502:physiology*; D015971:Gene Expression Regulation, Enzymologic; D008562:Membrane Glycoproteins / Q000235:genetics / Q000378:metabolism; D051379:Mice; D008822:Mice, Transgenic; D000074662:NADPH Oxidase 2; D019255:NADPH Oxidases / Q000235:genetics / Q000378:metabolism; D009569:Nitric Oxide / Q000378:metabolism; D052250:Nitric Oxide Synthase Type III / Q000235:genetics / Q000378:metabolism; D018384:Oxidative Stress; D017382:Reactive Oxygen Species; D058570:TOR Serine-Threonine Kinases / Q000235:genetics / Q000378:metabolism
chemical_list: D008562:Membrane Glycoproteins; D017382:Reactive Oxygen Species; D009569:Nitric Oxide; D052250:Nitric Oxide Synthase Type III; C496315:Nos3 protein, mouse; C488842:Cybb protein, mouse; D000074662:NADPH Oxidase 2; D019255:NADPH Oxidases; C546843:mTOR protein, mouse; D058570:TOR Serine-Threonine Kinases; D000263:Adenylate Kinase
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