Division of Cardiovascular Medicine, Kobe University Graduate School of Medicine, 7-5-1 Kusunoki-cho, Chuo-ku, Kobe, Japan.
Cardiovasc Res. 2010 Jul 15;87(2):385-93. doi: 10.1093/cvr/cvp419. Epub 2010 Jan 2.
In addition to their cholesterol-lowering effect, statins increase high-density lipoprotein cholesterol (HDL-C) levels. Endothelial lipase (EL) is a regulator of plasma HDL-C levels. In the present study, the effects of statins on EL expression were investigated.
The 3-hydroxy-3-methylglutaryl-coenzyme A reductase inhibitor pitavastatin suppressed basal and cytokine-treated EL expression in endothelial cells. Concomitant treatment with mevalonate or geranylgeranyl pyrophosphate completely reversed the inhibitory effect of pitavastatin, suggesting that geranylgeranylated proteins are involved in the inhibition of EL expression by statins. Inhibition of RhoA activity by overexpression of a dominant-negative mutant of RhoA or a Rho kinase inhibitor decreased EL levels. Pitavastatin reduced phospholipase activities of endothelial cells, and concomitant treatment with mevalonate reversed its inhibitory effect. Pitavastatin reduced RhoA activity and EL expression in mouse tissues. Furthermore, plasma EL concentrations in human subjects were measured by enzyme-linked immunosorbent assays. Plasma EL levels were negatively associated with plasma HDL levels in 237 patients with cardiovascular diseases, and pitavastatin treatment reduced plasma EL levels and increased HDL-C levels in 48 patients with hypercholesterolaemia.
These findings suggest that statins can reduce EL expression in vitro and in vivo via inhibition of RhoA activity. The inhibition of EL expression in the vessel wall may contribute to the anti-atherogenic effects of statins.
除了降低胆固醇的作用外，他汀类药物还能增加高密度脂蛋白胆固醇（HDL-C）水平。内皮脂肪酶（EL）是血浆 HDL-C 水平的调节因子。本研究旨在探讨他汀类药物对 EL 表达的影响。
3-羟基-3-甲基戊二酰辅酶 A 还原酶抑制剂匹伐他汀可抑制内皮细胞中基础状态和细胞因子处理后的 EL 表达。与甲羟戊酸或香叶基香叶基焦磷酸酯同时治疗完全逆转了匹伐他汀的抑制作用，表明香叶基化蛋白参与了他汀类药物对 EL 表达的抑制。通过过表达 RhoA 的显性负突变体或 Rho 激酶抑制剂抑制 RhoA 活性，可降低 EL 水平。匹伐他汀降低了内皮细胞的磷脂酶活性，而与甲羟戊酸同时治疗可逆转其抑制作用。匹伐他汀降低了小鼠组织中的 RhoA 活性和 EL 表达。此外，通过酶联免疫吸附试验测定了 237 例心血管疾病患者的血浆 EL 浓度。237 例心血管疾病患者的血浆 EL 水平与血浆 HDL 水平呈负相关，而匹伐他汀治疗可降低 48 例高胆固醇血症患者的血浆 EL 水平并升高 HDL-C 水平。
这些发现表明，他汀类药物可通过抑制 RhoA 活性来降低体外和体内的 EL 表达。血管壁中 EL 表达的抑制可能有助于他汀类药物的抗动脉粥样硬化作用。
