Abstract 13469: Alpha1-AMPK Deletion Enhances Endothelial Dysfunction and Vascular Oxidative Stress During Chronic Angiotensin II Treatment by Upregulation of Nox2
Background: AMP-activated protein kinase (AMPK) plays a pivotal role in cellular adaptation to decreased energy supply. In the vasculature, AMPK activates endothelial NO synthase, promotes angiogenesis and limits endothelial cell apoptosis as well as vascular smooth muscle cell proliferation. Since all of these processes play a fundamental role in vascular disease, we studied the effects of in vivo AMPK inhibition during chronic angiotensin II (ATII) treatment.
Methods and Results: Chronic angiotensin II infusion at subpressor doses (0.1mg/kg/d) resulted in vascular AMPK activation, which was attenuated in mice lacking the predominant vascular isoform alpha1AMPK. ATII treatment lead to a mild endothelial dysfunction, that was significantly further impaired in alpha1AMPK knockout mice. Unexpectedly, endothelial dysfunction after alpha1AMPK knockout was not associated with a decreased NO-production, since total NO-levels measured by plasma nitrite or EPR were even increased. In addition, we found that alpha1AMPK knockout augmented oxidative stress by promoting NADPH oxidase derived ROS production. The increased NOX activity was associated with a significant increase in NOX2 mRNA and protein expression. The involvement of NADPH oxidases in the development of endothelial dysfunction in alpha1AMPK knockout mice was further substantiated by additional in vivo treatment with apocynin, which attenuated angiotensin II-driven vascular oxidative stress and endothelial dysfunction.
Conclusions: In vivo AMPK inhibition during vascular disease impairs endothelial function by NOX2 upregulation and increased NADPH oxidase activity, suggesting AMPK activation as a protective molecular target in vascular homeostasis
- © 2010 by American Heart Association, Inc.