Gene transfer and hepatic overexpression of the HDL receptor SR-BI reduces atherosclerosis in the cholesterol-fed LDL receptor-deficient mouse
Gene transfer and hepatic overexpression of the HDL receptor SR-BI reduces atherosclerosis in the cholesterol-fed LDL receptor-deficient mouse
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DOI：
10.1161/01.atv.20.3.721
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发表时间：
2000-03-01
影响因子：
8.7
通讯作者：
Rader, DJ
中科院分区：
文献类型：
--
作者：
Kozarsky, KF;Donahee, MH;Rader, DJ
人类的高密度脂蛋白胆固醇水平与动脉粥样硬化的风险呈负相关。B类清道夫受体I(SR-BI)是第一个分子上定义明确的高密度脂蛋白受体，在正常小鼠肝脏中过表达SR-BI可导致血浆高密度脂蛋白水平降低。为了确定SR-BI的过度表达是导致动脉粥样硬化还是对动脉粥样硬化具有保护作用，将低密度脂蛋白受体缺陷小鼠置于高脂/高胆固醇饮食中2周或12周，诱导不同阶段的动脉粥样硬化病变，然后注射编码小鼠SR-BI的重组腺病毒。在早期和晚期病变的小鼠中，一过性的SR-BI的肝脏过度表达显著减少了动脉粥样硬化。SR-BI的表达与高密度脂蛋白胆固醇显著降低相关，而非高密度脂蛋白胆固醇水平不变或仅略有降低；在所有实验中，平均高密度脂蛋白胆固醇水平与动脉粥样硬化病变大小显著相关。这些数据表明，促进高密度脂蛋白胆固醇转运和降低血浆高密度脂蛋白水平的干预措施可以抑制动脉粥样硬化，即使在显著病变发生后开始干预也是如此。因此，刺激肝脏SR-BI活性可能为动脉粥样硬化性心血管疾病的治疗干预提供新的靶点。
HDL cholesterol levels in humans are inversely correlated with the risk of atherosclerosis. The class B scavenger receptor type I (SR-BI) is the first molecularly well-defined HDL receptor, and hepatic overexpression of SR-BI in normal mice has been shown to result in decreased plasma HDL cholesterol levels. To determine whether SR-BI overexpression is proatherogenic or is protective against atherosclerosis, LDL receptor-deficient mice were placed on a high-fat/high-cholesterol diet for 2 or 12 weeks to induce atherosclerotic lesions of different stages and then were injected with a recombinant adenovirus encoding murine SR-BI. Transient hepatic overexpression of SR-BI in mice with both early and advanced lesions significantly decreased atherosclerosis. SR-BI expression was associated with markedly decreased HDL cholesterol and either unchanged or only modestly reduced non-HDL cholesterol levels; in all experiments, the mean HDL cholesterol levels were significantly correlated with atherosclerotic lesion size. These data suggest that interventions that promote HDL cholesterol transport and lower plasma HDL cholesterol levels can suppress atherosclerosis, even when initiated after significant lesion development. Thus, stimulation of hepatic SR-BI activity may provide a novel target for therapeutic intervention in atherosclerotic cardiovascular disease.