Introduction: Cardiovascular disease represents an ongoing worldwide health problem with high mortality due to myocardial infarction, heart failure and stroke. In this respect, disease prevention is highly important and unraveling mechanism for vascular protection are necessary for the possible development of novel pharmacological treatment.Exercise training is an easy and effective way of maintaining vascular homeostasis. AMPK and specifically its subunit alpha1AMPK obtain multifunctional vascular protective effects by limiting ROS and regulating NO production in models of hypertension and vascular inflammation.Hypothesis:Exercise training and alpha1AMPK are associated with beneficial effects on vascular function. Consequences of endothelial specific alpha1AMPK deletion during exercise training remain elusive. Therefore we generated an endothelial specific alpha1AMPK knockout mouse and performed experiments after voluntary exercise training.
Methods: TekCre+ and alpha1AMPK (fl/fl) mice were crossed. Mice were placed in individual cages with treadmill for 8 weeks.Vascular relaxation was examined using organ chamber bathes.NO-measurements were done using ESR.ROS production was measured with DHE,Dot blot and HPLC. Cell Senescence was investigated with PCR, Apoptosis with tunel staining.
Results: Wild-type mice had an improved endothelial function after exercise training. Interestingly, our knockout mice developed an endothelial-dependent dysfunction. In line with this, we detected reduced vascular eNOS activity and NO production in these mice, accompanied with increased vascular ROS production.eNOS uncoupling and reduced vascular antioxidant response explained the aggravated vascular function and ROS production in our knockout animals. It turned out that endothelial specific alpha1AMPK deletion influences cell senescence by limiting telomerase activity and accelerated apoptosis.
Conclusions: Intact endothelial alpha1AMPK is necessary to maintain the vascular protective effects of exercise training. Pharmacological stimulation of endothelial alpha1AMPK might be a promising target to mimic the vascular protective effects of exercise training.