Ceolotto Giulio, Papparella Italia, Sticca Antonietta, Bova Sergio, Cavalli Maurizio, Cargnelli Gabriella, Semplicini Andrea, Gatta Angelo, Angeli Paolo
Department of Clinical and Experimental Medicine, University of Padova Medical School, Padova, Italy.
Hepatology. 2008 Dec;48(6):1913-23. doi: 10.1002/hep.22533.
Decreased cardiac contractility and beta-adrenergic responsiveness have been observed in cirrhotic cardiomyopathy, but their molecular mechanisms remain unclear. To study beta-adrenergic-stimulated contractility and beta-adrenergic gene expression patterns, 20 Wistar Kyoto rats were treated with carbon tetrachloride to induce cirrhosis and 20 rats were used as controls. Left ventricular contractility was recorded in electrically driven isolated hearts perfused at constant flow with isoproterenol (10(-10) to 10(-6) M). A cardiac gene expression profile was obtained using a microarray for the myocyte adrenergic pathway. The cardiac contractility maximal response to isoproterenol was significantly reduced in cirrhotic rats in comparison to control rats, whereas the half-maximal effective concentration was not different. In cirrhotic rats, cardiac gene expression analysis showed a significant overexpression of G protein alpha-inhibiting subunit 2 (Galpha(i2)), cyclic nucleotide phosphodiesterase (PDE2a), regulator of G-protein signaling 2 (RGS2), and down-expression of adenylate cyclase (Adcy3). These results indicate that overexpression of Galpha(i2), PDE2a, and RGS2 down-regulates the beta-adrenergic signaling pathway, thus contributing to the pathogenesis of cirrhotic cardiomyopathy.
在肝硬化性心肌病中已观察到心脏收缩力和β-肾上腺素能反应性降低，但其分子机制仍不清楚。为了研究β-肾上腺素能刺激的收缩力和β-肾上腺素能基因表达模式，将20只Wistar Kyoto大鼠用四氯化碳处理以诱导肝硬化，另20只大鼠作为对照。在以恒定流量灌注异丙肾上腺素（10^(-10)至10^(-6)M）的电驱动离体心脏中记录左心室收缩力。使用针对心肌细胞肾上腺素能途径的微阵列获得心脏基因表达谱。与对照大鼠相比，肝硬化大鼠对异丙肾上腺素的心脏收缩力最大反应显著降低，而半数最大有效浓度没有差异。在肝硬化大鼠中，心脏基因表达分析显示G蛋白α抑制亚基2（Gα(i2)）、环核苷酸磷酸二酯酶（PDE2a）、G蛋白信号调节剂2（RGS2）显著过表达，腺苷酸环化酶（Adcy3）表达下调。这些结果表明，Gα(i2)、PDE2a和RGS2的过表达下调了β-肾上腺素能信号通路，从而促进了肝硬化性心肌病的发病机制。
