Regression of atherosclerosis in apolipoprotein E-deficient mice is feasible using high-dose angiotensin receptor blocker, candesartan.
Regression of atherosclerosis in apolipoprotein E-deficient mice is feasible using high-dose angiotensin receptor blocker, candesartan.
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DOI：
10.5551/jat.12534
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发表时间：
2012
影响因子：
4.4
通讯作者：
Kaori Hayashi;H. Sasamura;T. Azegami;H. Itoh
中科院分区：
文献类型：
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作者：
Kaori Hayashi;H. Sasamura;T. Azegami;H. Itoh
目的临床研究表明，肾素-血管紧张素抑制剂对预防动脉粥样硬化进展是有效的，但对已建立的病变消退的结果是不确定的。本研究的目的是检查不同剂量的血管紧张素受体阻滞剂（ARB）坎地沙坦对载脂蛋白E（apoE）缺陷型自发性高脂血症（SHL）小鼠动脉粥样硬化和脂质诱导的肾病消退的影响。方法和结果雄性SHL给予致动脉粥样硬化饮食和盐负荷诱导动脉粥样硬化。然后用不同剂量的坎地沙坦（0-50 mg/kg/d）处理小鼠12周。高剂量坎地沙坦治疗可使主动脉粥样硬化斑块明显消退，而正常剂量坎地沙坦未观察到。双糖链蛋白聚糖和ACAT 1表达显著降低，主动脉游离胆固醇：胆固醇酯比在这些小鼠中增加。用坎地沙坦处理体外培养的THP-1巨噬细胞导致ACAT 1表达的类似降低。在肾脏，肾小球脂质积聚，系膜扩张和蛋白尿在高剂量坎地沙坦治疗后显著消退，而biglycan和ACAT 1表达降低。结论这些结果表明，使用高剂量坎地沙坦可以使ApoE缺陷小鼠中已建立的动脉粥样硬化病变消退，其机制包括（i）减少脂质保留蛋白多糖双糖链，和（ii）抑制ACAT 1表达，导致脂质释放的游离胆固醇增加。
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.