Lack of Endothelial α1AMPK Reverses the Vascular Protective Effects of Exercise by Causing eNOS Uncoupling

Antioxidants

Benoit Viollet¹  Marc Foretz¹  Eberhard Schulz²  Matthias Oelze³  Marin Kuntic³  Thomas Jansen³  Andreas Daiber³  Paul Stamm³  Miroslava Kvandová³  Thomas Münzel³  Isabella Schmal³  Sanela Kalinovic³  Swenja Kröller-Schön³  John F. Keaney⁴ 

[1] Centre National de la Recherche Scientifique (CNRS), Institut Cochin, INSERM, Université de Paris, 22, rue Mechain, F-75014 Paris, France;Department of Cardiology, AKH Celle, 29223 Celle, Germany;Department of Cardiology, University Medical Center Mainz, Johannes Gutenberg University, Langenbeckstr. 1, 55131 Mainz, Germany;Division of Cardiovascular Medicine, UMass Medical School, 55 Lake Avenue North, Worcester, MA 01655, USA;

关键词: α1AMPK;    endothelial cells;    exercise training;    reactive oxygen species;    endothelial dysfunction;   

DOI  :  10.3390/antiox10121974

来源: DOAJ

【 摘 要 】

Voluntary exercise training is an effective way to prevent cardiovascular disease, since it results in increased NO bioavailability and decreased reactive oxygen species (ROS) production. AMP-activated protein kinase (AMPK), especially its α1AMPK subunit, modulates ROS-dependent vascular homeostasis. Since endothelial cells play an important role in exercise-induced changes of vascular signaling, we examined the consequences of endothelial-specific α1AMPK deletion during voluntary exercise training. We generated a mouse strain with specific deletion of α1AMPK in endothelial cells (α1AMPK^flox/flox x TekCre⁺). While voluntary exercise training improved endothelial function in wild-type mice, it had deleterious effects in mice lacking endothelial α1AMPK indicated by elevated reactive oxygen species production (measured by dihydroethidum fluorescence and 3-nitrotyrosine staining), eNOS uncoupling and endothelial dysfunction. Importantly, the expression of the phagocytic NADPH oxidase isoform (NOX-2) was down-regulated by exercise in control mice, whereas it was up-regulated in exercising α1AMPK^flox/flox x TekCre⁺ animals. In addition, nitric oxide bioavailability was decreased and the antioxidant/protective nuclear factor erythroid 2-related factor 2 (Nrf-2) response via heme oxygenase 1 and uncoupling protein-2 (UCP-2) was impaired in exercising α1AMPK^flox/flox x TekCre⁺ mice. Our results demonstrate that endothelial α1AMPK is a critical component of the signaling events that enable vascular protection in response to exercise. Moreover, they identify endothelial α1AMPK as a master switch that determines whether the effects of exercise on the vasculature are protective or detrimental.

【 授权许可】

Unknown