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

Atherosclerosis. 2006 Feb;184(2):295-301. doi: 10.1016/j.atherosclerosis.2005.04.016. Epub 2005 Jul 6.

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.

Publication types

  • Comparative Study
  • Research Support, Non-U.S. Gov't
  • Research Support, U.S. Gov't, Non-P.H.S.

MeSH terms

  • Angiotensin II Type 1 Receptor Blockers / therapeutic use
  • Animals
  • Atherosclerosis / etiology
  • Atherosclerosis / metabolism*
  • Atherosclerosis / prevention & control
  • Benzimidazoles / therapeutic use*
  • Blotting, Western
  • Disease Models, Animal
  • Drug Synergism
  • Drug Therapy, Combination
  • Dyslipidemias / complications
  • Dyslipidemias / drug therapy*
  • Dyslipidemias / metabolism
  • Fluorobenzenes / therapeutic use*
  • Hydroxymethylglutaryl-CoA Reductase Inhibitors / therapeutic use
  • Mice
  • Mice, Inbred C57BL
  • Mice, Knockout
  • Mitogen-Activated Protein Kinases / biosynthesis*
  • Mitogen-Activated Protein Kinases / drug effects
  • Phosphorylation
  • Pyrimidines / therapeutic use*
  • Renin-Angiotensin System / physiology*
  • Rosuvastatin Calcium
  • Scavenger Receptors, Class E / biosynthesis*
  • Scavenger Receptors, Class E / drug effects
  • Sulfonamides / therapeutic use*
  • Tetrazoles / therapeutic use*

Substances

  • Angiotensin II Type 1 Receptor Blockers
  • Benzimidazoles
  • Fluorobenzenes
  • Hydroxymethylglutaryl-CoA Reductase Inhibitors
  • OLR1 protein, human
  • Pyrimidines
  • Scavenger Receptors, Class E
  • Sulfonamides
  • Tetrazoles
  • Rosuvastatin Calcium
  • Mitogen-Activated Protein Kinases
  • candesartan