Lack of Endothelial α1AMPK Reverses the Vascular Protective Effects of Exercise by Causing eNOS Uncoupling
2021
Thomas Jansen | Miroslava Kvandová | Isabella Schmal | Sanela Kalinovic | Paul Stamm | Marin Kuntic | Marc Foretz | Benoit Viollet | Andreas Daiber | Matthias Oelze | John F. Keaney | Thomas Münzel | Eberhard Schulz | Swenja Kröller-Schön
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 &alpha:1AMPK 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 &alpha:1AMPK deletion during voluntary exercise training. We generated a mouse strain with specific deletion of &alpha:1AMPK in endothelial cells (&alpha:1AMPKflox/flox x TekCre+). While voluntary exercise training improved endothelial function in wild-type mice, it had deleterious effects in mice lacking endothelial &alpha:1AMPK 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 &alpha:1AMPKflox/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 &alpha:1AMPKflox/flox x TekCre+ mice. Our results demonstrate that endothelial &alpha:1AMPK is a critical component of the signaling events that enable vascular protection in response to exercise. Moreover, they identify endothelial &alpha:1AMPK as a master switch that determines whether the effects of exercise on the vasculature are protective or detrimental.
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