Statin-specific inhibition of Rab-GTPase regulates cPKC-mediated IKs internalization
Statin-specific inhibition of Rab-GTPase regulates cPKC-mediated IKs internalization
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DOI：
10.1038/s41598-019-53700-6
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发表时间：
2019-11-28
影响因子：
4.6
通讯作者：
Lopes, Coeli M.
中科院分区：
文献类型：
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作者：
Ronzier, Elsa;Parks, Xiaorong Xu;Lopes, Coeli M.
他汀类药物用于预防和治疗冠状动脉疾病。他汀类药物具有不同的降胆固醇能力，其中瑞舒伐他汀和阿托伐他汀效果最好，而辛伐他汀和氟伐他汀等他汀类药物效果较差。他汀类药物除了具有降低胆固醇的作用外，还可以阻止Rab-GTPase蛋白的异戊二烯化，Rab-GTPase蛋白是调节膜结合蛋白运输的重要蛋白家族。本研究表明，rab - gtpase （Rab5、Rab7和Rab11）的内体定位以他汀类药物特异性的方式被抑制，氟伐他汀的作用较强，其次是辛伐他汀和阿托伐他汀，瑞舒伐他汀的作用有限。氟伐他汀抑制Rab5已被证明可介导心脏延迟整流KCNQ1/KCNE1通道的cpkc依赖性转运调节。我们在异源系统和心肌细胞中观察到他汀类药物特异性抑制通道调节与他汀类药物特异性rabb - gtpase抑制一致。我们的研究结果揭示了他汀类药物对降低胆固醇的非特异性作用。由于rab - gtpase是重要的膜运输调节因子，它们可能是他汀类药物特异性多效效应的基础。因此，他汀类药物的特异性可能允许更好的治疗定制。
Statins are prescribed for prevention and treatment of coronary artery disease. Statins have different cholesterol lowering abilities, with rosuvastatin and atorvastatin being the most effective, while statins like simvastatin and fluvastatin having lower effectiveness. Statins, in addition to their cholesterol lowering effects, can prevent isoprenylation of Rab-GTPase proteins, a protein family important for the regulation of membrane-bound protein trafficking. Here we show that endosomal localization of Rab-GTPases (Rab5, Rab7 and Rab11) was inhibited in a statin-specific manner, with stronger effects by fluvastatin, followed by simvastatin and atorvastatin, and with a limited effect by rosuvastatin. Fluvastatin inhibition of Rab5 has been shown to mediate cPKC-dependent trafficking regulation of the cardiac delayed rectifier KCNQ1/KCNE1 channels. We observed statin-specific inhibition of channel regulation consistent with statin-specific Rab-GTPase inhibition both in heterologous systems and cardiomyocytes. Our results uncover a non-cholesterol-reducing statin-specific effect of statins. Because Rab-GTPases are important regulators of membrane trafficking they may underlie statin specific pleiotropic effects. Therefore, statin-specificity may allow better treatment tailoring.