Abstract
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 (α1AMPKflox/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 α1AMPKflox/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 α1AMPKflox/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.
Highlights
Cardiovascular disease is associated with high mortality, despite broad treatment advances in this field [1,2]
Since endothelial cells play a prominent role for vascular homeostasis, the current study examines the effects of voluntary exercise training in an endothelial-specific α1AMPK knockout mouse model (α1AMPKflox/flox x TekCre+ )
Genetic deletion of α1AMPK in endothelial cells reduced protein expression by approximately 80% in α1AMPKflox/flox x TekCre+ mice compared to wild-type controls (Figure 1B) and a >90% reduction in α1AMPK gene expression was shown in mouse lung endothelial cells (MLEC); see Supplementary Figure S1. α1AMPK
Summary
Cardiovascular disease is associated with high mortality, despite broad treatment advances in this field [1,2]. Effective disease prevention would be capable of saving millions of patient lives and significantly reduce costs of our health system [3,4,5] In this respect, endothelial dysfunction represents a common hallmark in the genesis of Antioxidants 2021, 10, 1974. Among different forms of exercise training, “aerobic” voluntary exercise training is recognized as one of the most effective forms of disease prevention, since it promotes NO bioavailability and reduces oxidative stress in the vasculature. Both effects contribute to improved endothelial function and promote vascular health [10,11,12]
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