Regression of Atherosclerosis in Apolipoprotein E-Deficient Mice is Feasible Using High-Dose Angiotensin Receptor Blocker, Candesartan

Abstract

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. 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. 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.