Regression of atherosclerosis in apolipoprotein E-deficient mice is feasible using high-dose angiotensin receptor blocker, candesartan.

Abstract

AIM:

Clinical studies have suggested that renin-angiotensin inhibitors are effective for the prevention of atherosclerosis progression, but the results for the regression of established lesions are equivocal. The aim of this study was to examine the effects of different doses of the angiotensin receptor blocker (ARB) candesartan on the regression of atherosclerosis and lipid-induced nephropathy in apolipoprotein E (apoE)-deficient spontaneously hyperlipidemic (SHL) mice.

METHODS AND RESULTS:

Male SHL were given an atherogenic diet together with salt loading to induce atherosclerosis. The mice were then treated with various doses of candesartan (0-50 mg/kg/d) for 12 weeks. Treatment with high-dose candesartan caused clear regression of atherosclerotic plaques in the aorta, which was not observed with normal-dose candesartan. Biglycan and ACAT1 expression were significantly decreased, and aortic free cholesterol: cholesterol ester ratios were increased in these mice. Treatment of cultured THP-1 macrophages in vitro with candesartan resulted in a similar decrease in ACAT1 expression. In the kidney, glomerular lipid accumulation, mesangial expansion, and albuminuria were significantly regressed after treatment with high-dose candesartan, while biglycan and ACAT1 expressions were decreased.

CONCLUSION:

These results suggest that regression of established atherosclerosis lesions in ApoE-deficient mice is feasible using high-dose candesartan, by mechanisms involving (i) a decrease in the lipid-retaining proteoglycan biglycan, and (ii) suppression of ACAT1 expression resulting in increased free cholesterol for lipid release.

• Authors: Kaori Hayashi, Hiroyuki Sasamura, Tatsuhiko Azegami, Hiroshi Itoh
• Journal: Journal of atherosclerosis and thrombosis (J Atheroscler Thromb) Vol. 19 Issue 8 Pg. 736-46 ( 2012) ISSN: 1880-3873 [Electronic] Japan
• PMID: 22576470 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)

Chemical References

• Angiotensin Receptor Antagonists
• Apolipoproteins E
• Benzimidazoles
• Biphenyl Compounds
• Tetrazoles
• Acat1 protein, mouse
• Acetyl-CoA C-Acetyltransferase
• candesartan

Topics

• Acetyl-CoA C-Acetyltransferase (metabolism)
• Angiotensin Receptor Antagonists (therapeutic use)
• Animals
• Apolipoproteins E (physiology)
• Atherosclerosis (etiology, prevention & control)
• Benzimidazoles (therapeutic use)
• Biphenyl Compounds
• Blotting, Western
• Fluorescent Antibody Technique
• Hyperlipidemias (etiology, pathology)
• Kidney Diseases (etiology, prevention & control)
• Male
• Mice
• Mice, Inbred C57BL
• Mice, Knockout
• Monocytes (metabolism, pathology)
• Tetrazoles (therapeutic use)