title: Cross-talk between dyslipidemia and renin-angiotensin system and the role of LOX-1 and MAPK in atherogenesis studies with the combined use of rosuvastatin and candesartan.
abstract: There is increasing evidence of cross-talk between dyslipidemia and renin-angiotensin system (RAS) in atherogenesis. Both dyslipidemia and RAS activation enhance the expression of a newly described receptor for oxidized-low density lipoprotein (ox-LDL), lectin-like ox-LDL receptor-1 (LOX-1). We postulated that the blockade of dyslipidemia with rosuvastatin, a 3-hydroxy-3-methylglutaryl coenzyme A reductase inhibitor and RAS with candesartan, an angiotensin II type 1 receptor blocker, would have a synergistic inhibitory effect on LOX-1 expression and atherogenesis. Apo-E knockout mice were fed a high-cholesterol diet (1% cholesterol, HC-diet) alone, or HC-diet with rosuvastatin (1mg/(kgd)), candesartan (1mg/(kgd)) or with both. Twelve weeks later the extent of atherosclerosis was determined by Sudan IV staining. Apo-E knockout mice on HC-diet had extensive atherosclerosis. Both rosuvastatin and candesartan decreased the extent of atherosclerosis (by 23 and 26%, respectively), despite the HC-diet; however, the combination of rosuvastatin and candesartan reduced atherosclerosis further (by 67%). Rosuvastatin decreased plasma levels of total cholesterol by over 50%, whereas candesartan had no effect. LOX-1 protein expression was found to be markedly up-regulated in HC-diet-fed apo-E knockout mice. While rosuvastatin and candesartan each had a small inhibitory effect on the expression of LOX-1 in the atherosclerotic tissues, the combination totally blocked the up-regulation of LOX-1. P38 mitogen-activated protein kinase (MAPK) expression and phosphorylation were increased in apo-E knockout mice, attenuated by rosuvastatin or candesartan alone, and completely blocked by the combination of the two agents. P44/42 MAPK expression and phosphorylation were not affected by the HC-diet, rosuvastatin, candesartan, or their combination. This study demonstrates the potent effect of rosuvastatin and candesartan on atherogenesis, as well as on the expression of LOX-1 and on the activation of p38 MAPK, but not p44/42 MAPK.
authors: Department of Internal Medicine, University of Arkansas for Medical Sciences and Central Arkansas Veterans Healthcare System, Little Rock, AR 72205, USA.
authors: Jiawei
authors: J
authors: Chen
authors: Dayuan
authors: D
authors: Li
authors: Robert
authors: R
authors: Schaefer
authors: Jawahar L
authors: JL
authors: Mehta
mesh_terms: D047228:Angiotensin II Type 1 Receptor Blockers / Q000627:therapeutic use; D000818:Animals; D050197:Atherosclerosis / Q000209:etiology / Q000378:metabolism* / Q000517:prevention & control; D001562:Benzimidazoles / Q000627:therapeutic use*; D001713:Biphenyl Compounds; D015153:Blotting, Western; D004195:Disease Models, Animal; D004357:Drug Synergism; D004359:Drug Therapy, Combination; D050171:Dyslipidemias / Q000150:complications / Q000188:drug therapy* / Q000378:metabolism; D005464:Fluorobenzenes / Q000627:therapeutic use*; D019161:Hydroxymethylglutaryl-CoA Reductase Inhibitors / Q000627:therapeutic use; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D020928:Mitogen-Activated Protein Kinases / Q000096:biosynthesis* / Q000187:drug effects; D010766:Phosphorylation; D011743:Pyrimidines / Q000627:therapeutic use*; D012084:Renin-Angiotensin System / Q000502:physiology*; D000068718:Rosuvastatin Calcium; D051127:Scavenger Receptors, Class E / Q000096:biosynthesis* / Q000187:drug effects; D013449:Sulfonamides / Q000627:therapeutic use*; D013777:Tetrazoles / Q000627:therapeutic use*
chemical_list: D047228:Angiotensin II Type 1 Receptor Blockers; D001562:Benzimidazoles; D001713:Biphenyl Compounds; D005464:Fluorobenzenes; D019161:Hydroxymethylglutaryl-CoA Reductase Inhibitors; C495137:OLR1 protein, human; D011743:Pyrimidines; D051127:Scavenger Receptors, Class E; D013449:Sulfonamides; D013777:Tetrazoles; D000068718:Rosuvastatin Calcium; D020928:Mitogen-Activated Protein Kinases; C081643:candesartan