Trebicka Jonel, Hennenberg Martin, Laleman Wim, Shelest Nataliya, Biecker Erwin, Schepke Michael, Nevens Frederik, Sauerbruch Tilman, Heller Jörg
Department of Internal Medicine I, University of Bonn, Bonn, Germany.
Hepatology. 2007 Jul;46(1):242-53. doi: 10.1002/hep.21673.
In cirrhosis, increased RhoA/Rho-kinase signaling and decreased nitric oxide (NO) availability contribute to increased intrahepatic resistance and portal hypertension. Hepatic stellate cells (HSCs) regulate intrahepatic resistance. 3-Hydroxy-3-methylglutaryl coenzyme A reductase inhibitors (statins) inhibit synthesis of isoprenoids, which are necessary for membrane translocation and activation of small GTPases like RhoA and Ras. Activated RhoA leads to Rho-kinase activation and NO synthase inhibition. We therefore investigated the effects of atorvastatin in cirrhotic rats and isolated HSCs. Rats with secondary biliary cirrhosis (bile duct ligation, BDL) were treated with atorvastatin (15 mg/kg per day for 7 days) or remained untreated. Hemodynamic parameters were determined in vivo (colored microspheres). Intrahepatic resistance was investigated in in situ perfused livers. Expression and phosphorylation of proteins were analyzed by RT-PCR and immunoblots. Three-dimensional stress-relaxed collagen lattice contractions of HSCs were performed after incubation with atorvastatin. Atorvastatin reduced portal pressure without affecting mean arterial pressure in vivo. This was associated with a reduction in intrahepatic resistance and reduced responsiveness of in situ-perfused cirrhotic livers to methoxamine. Furthermore, atorvastatin reduced the contraction of activated HSCs in a 3-dimensional stress-relaxed collagen lattice. In cirrhotic livers, atorvastatin significantly decreased Rho-kinase activity (moesin phosphorylation) without affecting expression of RhoA, Rho-kinase and Ras. In activated HSCs, atorvastatin inhibited the membrane association of RhoA and Ras. Furthermore, in BDL rats, atorvastatin significantly increased hepatic endothelial nitric oxide synthase (eNOS) mRNA and protein levels, phospho-eNOS, nitrite/nitrate, and the activity of the NO effector protein kinase G (PKG).
In cirrhotic rats, atorvastatin inhibits hepatic RhoA/Rho-kinase signaling and activates the NO/PKG-pathway. This lowers intrahepatic resistance, resulting in decreased portal pressure. Statins might represent a therapeutic option for portal hypertension in cirrhosis.
在肝硬化中，RhoA/ Rho激酶信号增强和一氧化氮（NO）可用性降低会导致肝内阻力增加和门静脉高压。肝星状细胞（HSC）调节肝内阻力。3-羟基-3-甲基戊二酰辅酶A还原酶抑制剂（他汀类药物）抑制类异戊二烯的合成，而类异戊二烯是小GTP酶（如RhoA和Ras）膜易位和激活所必需的。活化的RhoA导致Rho激酶活化和NO合酶抑制。因此，我们研究了阿托伐他汀对肝硬化大鼠和分离的HSC的影响。继发性胆汁性肝硬化（胆管结扎，BDL）大鼠接受阿托伐他汀治疗（每天15mg/kg，共7天）或不治疗。在体内测定血流动力学参数（彩色微球）。在原位灌注肝脏中研究肝内阻力。通过RT-PCR和免疫印迹分析蛋白质的表达和磷酸化。用阿托伐他汀孵育后，对HSC进行三维应力松弛胶原晶格收缩实验。阿托伐他汀在体内降低门静脉压力而不影响平均动脉压。这与肝内阻力降低和原位灌注肝硬化肝脏对甲氧明的反应性降低有关。此外，阿托伐他汀在三维应力松弛胶原晶格中降低了活化HSC的收缩。在肝硬化肝脏中，阿托伐他汀显著降低Rho激酶活性（肌动蛋白磷酸化），而不影响RhoA、Rho激酶和Ras的表达。在活化的HSC中，阿托伐他汀抑制RhoA和Ras的膜结合。此外，在BDL大鼠中，阿托伐他汀显著增加肝内皮一氧化氮合酶（eNOS）mRNA和蛋白水平、磷酸化eNOS、亚硝酸盐/硝酸盐以及NO效应蛋白激酶G（PKG）的活性。
在肝硬化大鼠中，阿托伐他汀抑制肝脏RhoA/ Rho激酶信号传导并激活NO/PKG途径。这降低了肝内阻力，导致门静脉压力降低。他汀类药物可能是肝硬化门静脉高压的一种治疗选择。
