Published Online
on January 17, 2005

A more recent version of this article appeared on February 1, 2005

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Submitted on June 20, 2004
Revised on July 8, 2004

Angiotensin II Type-1 Receptor Antagonism Attenuates the Inflammatory and Thrombogenic Responses to Hypercholesterolemia in Venules

Thomas Petnehazy; Karen Y. Stokes; Janice M. Russell; and D. Neil Granger^*

From the Department of Molecular and Cellular Physiology, Louisiana State University Health Sciences Center, Shreveport (K.Y.S., J.M.R., D.N.G.); and University Klinik for Pediatric Surgery (T.P.), University of Graz, Austria.

^* To whom correspondence should be addressed. E-mail: dgrang{at}lsuhsc.edu.

Abstract--Hypercholesterolemia elicits an inflammatory response in the microvasculature that is accompanied by an increased expression of angiotensin II type-1 receptors (AT1-R) on platelets, leukocytes, and endothelial cells. AT1-R blockade attenuates inflammatory responses to angiotensin II (eg, adhesion molecule expression and reactive oxygen species production). We investigated whether AT1-R antagonism attenuates the platelet and leukocyte recruitment induced by acute hypercholesterolemia in postcapillary venules. Leukocyte and platelet adhesion and oxidative stress were quantified by intravital microscopy in cremaster muscle, and P-selectin and AT1-R expression was determined in mice placed on a normal diet (ND) or high-cholesterol diet (HCD) for 2 weeks. Platelet and leukocyte adhesion was significantly elevated by hypercholesterolemia. In HCD mice receiving losartan (HCD-Los) in drinking water, platelet and leukocyte recruitment was reduced to ND levels. Increased platelet adhesion was observed in HCD mice receiving platelets from HCD-Los mice, consistent with a direct beneficial action of losartan on the vessel wall. Hypercholesterolemia elicited an oxidative stress in venules and an increased expression of P-selectin and AT1-R. The oxidative stress and AT1-R upregulation were reduced by losartan, but the P-selectin response was not. We propose that AT1-R engagement contributes to the prothrombogenic and proinflammatory state induced in venules by hypercholesterolemia.

Key words: receptors, angiotensin II • microcirculation • hypercholesterolemia • leukocytes

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