Leptin receptor blockade reduces intrahepatic vascular resistance and portal pressure in an experimental model of rat liver cirrhosis
Leptin receptor blockade reduces intrahepatic vascular resistance and portal pressure in an experimental model of rat liver cirrhosis
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DOI：
10.1152/ajpgi.00336.2012
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发表时间：
2013-10-01
影响因子：
4.5
通讯作者：
Carlos Garcia-Pagan, Juan
中科院分区：
文献类型：
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作者：
Gabriela Delgado, Maria;Gracia-Sancho, Jordi;Carlos Garcia-Pagan, Juan
主要由于血管张力升高和纤维化引起的肝血管阻力增加是肝硬化门静脉高压症发展的主要因素。瘦素是一种与一氧化氮生物利用度降低、血管功能障碍和肝纤维化相关的激素，在肝硬化患者中增加。我们的目的是评估瘦素是否影响门静脉高压症的肝阻力增加。四氯化碳中毒大鼠接受瘦素受体阻断剂ObR抗体，或其车辆，每隔一天1周。检测两组患者的肝脏和全身血流动力学。肝一氧化氮的生产和生物利用度，以及氧化应激，硝基酪氨酸蛋白质，肝纤维化，进行了评价。在肝硬化大鼠，瘦素受体阻滞剂显着降低门静脉压力，而不修改门静脉血流量，这表明在肝内阻力减少。门静脉压力降低与一氧化氮生物利用度增加以及O-2（-）水平和硝基酪氨酸化蛋白质降低相关。未观察到全身血流动力学和肝纤维化的变化。总之，目前的研究表明，肝硬化患者阻断瘦素信号通路可显著降低门静脉压力。这种效应可能是由于一氧化氮介导的肝血管张力降低。
Increased hepatic vascular resistance mainly due to elevated vascular tone and to fibrosis is the primary factor in the development of portal hypertension in cirrhosis. Leptin, a hormone associated with reduction in nitric oxide bioavailability, vascular dysfunction, and liver fibrosis, is increased in patients with cirrhosis. We aimed at evaluating whether leptin influences the increased hepatic resistance in portal hypertension. CCl4-cirrhotic rats received the leptin receptor-blocker ObR antibody, or its vehicle, every other day for 1 wk. Hepatic and systemic hemodynamics were measured in both groups. Hepatic nitric oxide production and bioavailability, together with oxidative stress, nitrotyrosinated proteins, and liver fibrosis, were evaluated. In cirrhotic rats, leptin-receptor blockade significantly reduced portal pressure without modifying portal blood flow, suggesting a reduction in the intrahepatic resistance. Portal pressure reduction was associated with increased nitric oxide bioavailability and with decreased O-2(-) levels and nitrotyrosinated proteins. No changes in systemic hemodynamics and liver fibrosis were observed. In conclusion, the present study shows that blockade of the leptin signaling pathway in cirrhosis significantly reduces portal pressure. This effect is probably due to a nitric oxide-mediated reduction in the hepatic vascular tone.