Angiotensin II type-1 receptor antagonism attenuates the inflammatory and thrombogenic responses to hypercholesterolemia in venules.
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.
Petnehazy
Thomas
T
Department of Molecular and Cellular Physiology, Louisiana State University Health Sciences Center, 1501 E Kings Highway, Shreveport, LA 71130-3932, USA.
Stokes
Karen Y
KY
Russell
Janice M
JM
Granger
D Neil
DN
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
D047228:Angiotensin II Type 1 Receptor Blockers; D016877:Oxidants; D019007:P-Selectin; D044140:Receptor, Angiotensin, Type 1; D019808:Losartan