title: Angiotensin II type-1 receptor antagonism attenuates the inflammatory and thrombogenic responses to hypercholesterolemia in venules.
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.
authors.affiliation: Department of Molecular and Cellular Physiology, Louisiana State University Health Sciences Center, 1501 E Kings Highway, Shreveport, LA 71130-3932, USA.
authors.forename: Thomas
authors.initials: T
authors.lastname: Petnehazy
authors.forename: Karen Y
authors.initials: KY
authors.lastname: Stokes
authors.forename: Janice M
authors.initials: JM
authors.lastname: Russell
authors.forename: D Neil
authors.initials: DN
authors.lastname: Granger
mesh_terms: D047228:Angiotensin II Type 1 Receptor Blockers / Q000494:pharmacology*; D000818:Animals; D001792:Blood Platelets / Q000378:metabolism; D002465:Cell Movement; D004730:Endothelium, Vascular / Q000378:metabolism; D006937:Hypercholesterolemia / Q000150:complications* / Q000503:physiopathology; D007962:Leukocytes; D019808:Losartan / Q000494:pharmacology*; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D016877:Oxidants / Q000096:biosynthesis; D019007:P-Selectin / Q000378:metabolism; D010973:Platelet Adhesiveness; D044140:Receptor, Angiotensin, Type 1 / Q000097:blood / Q000378:metabolism; D013927:Thrombosis / Q000209:etiology / Q000517:prevention & control*; D014657:Vasculitis / Q000209:etiology / Q000517:prevention & control*; D014699:Venules / Q000187:drug effects* / Q000378:metabolism
chemical_list: D047228:Angiotensin II Type 1 Receptor Blockers; D016877:Oxidants; D019007:P-Selectin; D044140:Receptor, Angiotensin, Type 1; D019808:Losartan