Abstract 3391: Knockout Of The Alpha1-amp-activated Protein Kinase Enhances Endothelial Dysfunction, Oxidative Stress And Vascular Inflammation During Chronic Angiotensin Ii Treatment
AMP-activated protein kinase (AMPK) plays a pivotal role in cellular adaptation to decreased energy supply and has been established as a molecular target in the treatment of diabetes. In the vasculature, AMPK activates endothelial NO synthase, promotes angiogenesis and limits endothelial cell apoptosis as well as vascular smooth muscle 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 (AT II) treatment. Chronic AT II treatment at subpressor doses (0.1mg/kg/d) resulted in vascular AMPK activation that was attenuated in mice lacking the predominant vascular isoform alpha1AMPK. While untreated alpha1AMPK knockout displayed no change in endothelial dysfunction, chronic AT II treatment lead to a significant impairment of endothelial function compared to wildtype mice that was not associated with a decreased NO-production. In contrast, we found that alpha1AMPK knockout augmented oxidative stress by promoting NADPH oxidase derived reactive oxygen species (ROS) production, associated with a significant increase in NOX-2 mRNA and protein expression. Since NOX-2 is the major component of phagocytic NADPH oxidases, we investigated whether loss of AMPK activity might propagate macrophage infiltration and other pro-inflammatory processes. In accordance with this notion, we found an upregulation of iNOS, VCAM and COX-2 in alpha1AMPK knockout mice treated with AT II indicating increased vascular inflammation. In vivo AMPK inhibition during vascular disease impairs endothelial function by augmenting vascular oxidative stress and vascular inflammation, but is independent of vascular NO production. Our results define AMPK as a protective molecular element during vascular disease.