Abstract 17741: Angiotensin II Enables Leukocyte/Endothelium Integrated Signaling Mechanisms That are Causative of Endothelial Dysfunction in Insulin Resistance
Recent studies have linked vascular AngII/AT1r signaling to the calcium-dependent protease µ-calpain. We have recently reported that activation of endothelial-expressed µ-calpain by AngII/AT1r signaling induces leukocyte-endothelium interactions in the post-capillary venules of the microcirculation. Accordingly, we hypothesized that: 1) AngII/calpain signaling impairs endothelium-dependent relaxation in the arterial system of the obese, insulin resistant Zucker Fatty (ZF) rat, and 2) neutrophil derived myeloperoxidase (MPO) synergizes with AngII/AT1r signaling to sustain calpain activation in the vascular wall of ZF rats. We used wire myography to study endothelium-dependent relaxation and vascular reactivity of the rat and mouse aorta. Aortic rings isolated from ZF rats exhibited reduced endothelium-dependent relaxation to ACh and increased contractility to Norepinephrine (p<0.01 versus control Lean Zucker (ZL) rats). Incubation of aortic rings with either 1-µm AT1r blocker losartan or 10-µM calpain inhibitor ZLLal restored endothelium-dependent relaxation in aortic rings from ZF rats (p<0.05 versus untreated ZF aortic rings). Furthermore, endothelium-dependent relaxation to ACh was preserved in µ-calpain deficient mice fed a high-fat diet for 12 consecutive weeks. Plasma and aortic levels of MPO were also elevated in ZF rats (p<0.01 versus ZL rats) and reduced by losartan treatment (p<0.05 versus untreated ZF rat). Ex vivo studies demonstrated that AngII acutely induces MPO release from control neutrophils, a phenomenon that was prevented by pre-incubation of neutrophils with 1-µM Losartan. Biochemical studies in rat aortic endothelial cells confirmed that MPO significantly synergizes AngII/AT1r-induced calpain activation. Taken together our data demonstrate that AngII/AT1r signaling impairs endothelium-dependent relaxation in the obese, insulin resistant organism by a mechanism that implicates neutrophil-derived MPO and endothelial expressed calpain. These data uncover: 1) a novel integrative mechanisms responsible for hypertension in obesity with insulin resistance and 2) new molecular targets of the pleiotropic actions of AT1r blocker on the blood-vascular system.
- © 2011 by American Heart Association, Inc.