Lack of Endothelial α1AMPK Reverses the Vascular Protective Effects of Exercise by Causing eNOS Uncoupling.
Thomas JansenMiroslava KvandováIsabella SchmalSanela KalinovicPaul StammMarin KunticMarc ForetzBenoit ViolletAndreas DaiberMatthias OelzeJohn F KeaneyThomas MunzelEberhard SchulzSwenja Kröller-SchönPublished in: Antioxidants (Basel, Switzerland) (2021)
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.
Keyphrases
- protein kinase
- endothelial cells
- skeletal muscle
- reactive oxygen species
- cardiovascular disease
- wild type
- nitric oxide
- high intensity
- nuclear factor
- nitric oxide synthase
- insulin resistance
- dna damage
- poor prognosis
- resistance training
- immune response
- inflammatory response
- toll like receptor
- small molecule
- body composition
- binding protein
- pi k akt
- long non coding rna
- amino acid
- single molecule
- protein protein