Atorvastatin desensitizes β-adrenergic signaling in cardiac myocytes via reduced isoprenylation of G-protein γ-subunits
Atorvastatin desensitizes β-adrenergic signaling in cardiac myocytes via reduced isoprenylation of G-protein γ-subunits
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DOI：
10.1096/fj.05-5067fje
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发表时间：
2006-02-01
期刊：
影响因子：
4.8
通讯作者：
Eschenhagen, Thomas
中科院分区：
文献类型：
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作者：
Muelhaeuser, Ulrike;Zolk, Oliver;Eschenhagen, Thomas
他汀类药物通过减少单体GTP酶的异戊二烯基化而发挥多效性、非胆固醇依赖性的作用。在这里，我们研究了他汀类药物是否也减少了异三聚体G蛋白的伽马亚基的异戊二烯基化，从而影响了心肌细胞中的β-肾上腺素能信号和力的调节。用阿托伐他汀(0.1~10mU/L，12~48h)处理乳鼠心肌细胞，检测腺苷环化酶对G蛋白α(Gα)、β(Gβ)和γ(Gγ)亚单位的调节作用及cAMP积聚。来自NRCM的工程化心脏组织(EHT)用于评估收缩效果。在阿托伐他汀处理的NRCM中，第二条表观分子量较低的G-Gamma 3出现在细胞质和颗粒组分中，这在赋形剂处理的NRCM中是没有的，但在香叶基香叶转移酶抑制剂GGTI-298后也能看到。同时，Gβ在胞浆中积累，细胞内GAS的总含量减少。在阿托伐他汀治疗的NRCM中，异丙肾上腺素增加cAMP的作用减弱。同样，异丙肾上腺素的正性肌力作用在阿托伐他汀治疗后脱敏和减弱。阿托伐他汀的作用可被甲羟戊酸和/或香叶基焦磷酸消除，但不能被法尼基焦磷酸或角鲨烯所消除。综上所述，本研究的结果表明，阿托伐他汀通过减少Gγ的异丙二烯基化和随后减少GαS的细胞含量来降低NRCM对β-肾上腺素能刺激的敏感性。
Statins exert pleiotropic, cholesterol-independent effects by reducing isoprenylation of monomeric GTPases. Here we examined whether statins also reduce isoprenylation of gamma-subunits of heterotrimeric G-proteins and thereby affect beta-adrenergic signaling and regulation of force in cardiac myocytes. Neonatal rat cardiac myocytes (NRCM) were treated with atorvastatin (0.1- 10 mu mol/l; 12-48 h) and examined for adenylyl cyclase regulating G-protein alpha- (G alpha), beta- (G beta), and gamma- (G gamma) subunits and cAMP accumulation. Engineered heart tissue (EHT) from NRCM was used to evaluate contractile consequences. In atorvastatin-treated NRCM, a second band of G gamma 3 with a lower apparent molecular weight appeared in cytosol and particulate fractions that was absent in vehicle-treated NRCM, but also seen after GGTI-298, a geranylgeranyl transferase inhibitor. In parallel, G beta accumulated in the cytosol and total cellular content of Gas was reduced. In atorvastatin-treated NRCM, the cAMP-increasing effect of isoprenaline was reduced. Likewise, the positive inotropic effect of isoprenaline was desensitized and reduced after treatment with atorvastatin. The effects of atorvastatin were abolished by mevalonate and/or geranylgeranyl pyrophosphate, but not by farnesyl pyrophosphate or squalene. Taken together, the results of this study show that atorvastatin desensitizes NRCM to beta-adrenergic stimulation by a mechanism that involves reduced isoprenylation of G gamma and subsequent reductions in the cellular content of G alpha s.