Attenuation of tissue P-selectin and MCP-1 expression and intimal proliferation by AT(1) receptor blockade in hyperlipidemic rabbits.
Angiotensin-II (Ang-II) participates in the development and progression of atherosclerosis by activating type 1 (AT(1)) receptors. In vitro studies show that inflammatory factors, such as P-selectin and MCP-1, which can be upregulated by Ang-II, play an important role in atherogenesis. We examined the effect of AT(1) receptor blockade with losartan on the expression of P-selectin and MCP-1 in hypercholesterolemic rabbits. Since AT(1) receptor blockade is associated with feedback upregulation of renin-angiotensin system (RAS), we also examined alterations in plasma Ang-II levels by losartan therapy. Male NZW rabbits were fed regular chow (high cholesterol diet or high cholesterol diet + losartan 25 mg/kg/day). As expected, there was a marked intimal proliferation in association with increase in serum cholesterol (P < 0.001). In addition, there was a modest increase in plasma Ang-II levels (P < 0.05), and a significant increase in the expression of AT(1) receptors, P-selectin and MCP-1 in aortas of high cholesterol diet rabbits. Concurrent administration of losartan with high cholesterol diet attenuated aortic intimal proliferation induced a fivefold increase in plasma Ang-II levels and caused a marked decrease in expression of P-selectin and MCP-1 without change in serum lipid levels and aortic AT(1) receptor expression. These observations in hypercholesterolemic animal models show that AT(1) receptor blockade is associated with modulation of P-selectin and MCP-1 expression concurrent with reduction in intimal proliferation. The rise in plasma Ang-II does not appear to limit the potential beneficial effect of losartan.
Chen
H J
HJ
Department of Internal Medicine and Physiology, University of Arkansas for Medical Sciences, Little Rock, Arkansas 72205-7199, USA.
Li
D Y
DY
Saldeen
T
T
Phillips
M I
MI
Mehta
J L
JL
D000804:Angiotensin II / Q000097:blood; D057911:Angiotensin Receptor Antagonists; D000818:Animals; D001011:Aorta / Q000187:drug effects / Q000378:metabolism / Q000473:pathology; D001161:Arteriosclerosis / Q000209:etiology / Q000517:prevention & control; D018932:Chemokine CCL2 / Q000378:metabolism*; D004036:Diet, Atherogenic; D006949:Hyperlipidemias / Q000150:complications / Q000188:drug therapy / Q000378:metabolism* / Q000473:pathology*; D019808:Losartan / Q000494:pharmacology; D008297:Male; D019007:P-Selectin / Q000378:metabolism*; D011817:Rabbits; D044140:Receptor, Angiotensin, Type 1; D044139:Receptor, Angiotensin, Type 2
D057911:Angiotensin Receptor Antagonists; D018932:Chemokine CCL2; D019007:P-Selectin; D044140:Receptor, Angiotensin, Type 1; D044139:Receptor, Angiotensin, Type 2; D000804:Angiotensin II; D019808:Losartan