Principe Alessandro, Melgar-Lesmes Pedro, Fernández-Varo Guillermo, del Arbol Luis Ruiz, Ros Josefa, Morales-Ruiz Manuel, Bernardi Mauro, Arroyo Vicente, Jiménez Wladimiro
Biochemistry and Molecular Genetics Service, Centro de Investigación Biomédica en Red de Enfermedades Hepáticas y Digestivas (CIBEREHD), Hospital Clínic, University of Barcelona, Barcelona, Spain.
Hepatology. 2008 Oct;48(4):1193-201. doi: 10.1002/hep.22467.
Apelin is a peptide that plays an important role in heart physiology and pathophysiology, inflammation, and angiogenesis. We evaluated whether the endogenous apelin system is involved in the pathogenesis of the hepatic remodeling and cardiovascular and renal complications occurring in advanced liver disease. The circulating levels of apelin, the messenger RNA (mRNA) and protein expression of apelin and apelin receptor, the immunohistological detection of apelin and apelin receptor, and the effects induced by the chronic administration of an apelin receptor antagonist on fibrosis and vessel density were evaluated in rats with cirrhosis and ascites and in control rats. The serum levels of apelin in patients with cirrhosis were also measured. Apelin levels were higher in rats with cirrhosis than in controls. Apelin mRNA showed a four-fold rise only in hepatic tissue, but not in the lung, heart, or kidney of rats with cirrhosis. These animals also showed hepatic apelin receptor mRNA levels 300 times higher than controls. Apelin was highly expressed by stellate cells, whereas apelin receptor was overexpressed in the hepatic parenchyma of animals with cirrhosis. Rats with cirrhosis treated with the apelin receptor antagonist showed diminished hepatic fibrosis and vessel density, improved cardiovascular performance, and renal function and lost ascites. Human patients also showed a marked increase in apelin levels.
The selective hepatic activation of the apelin system, together with the drop in fibrosis and neoangiogenesis and the improvement in cardiovascular and excretory function resulting from apelin receptor blockade, points to the hepatic apelin system as a novel therapeutic target in liver disease.
阿片肽是一种在心脏生理与病理生理、炎症及血管生成中发挥重要作用的肽。我们评估了内源性阿片肽系统是否参与晚期肝病中发生的肝重塑以及心血管和肾脏并发症的发病机制。在肝硬化腹水大鼠和对照大鼠中，评估了阿片肽的循环水平、阿片肽及其受体的信使核糖核酸（mRNA）和蛋白表达、阿片肽及其受体的免疫组织学检测，以及长期给予阿片肽受体拮抗剂对纤维化和血管密度的影响。还测定了肝硬化患者血清中的阿片肽水平。肝硬化大鼠的阿片肽水平高于对照组。阿片肽mRNA仅在肝硬化大鼠的肝组织中呈四倍升高，而在其肺、心脏或肾脏中未升高。这些动物的肝脏阿片肽受体mRNA水平也比对照组高300倍。星状细胞高度表达阿片肽，而阿片肽受体在肝硬化动物的肝实质中过表达。用阿片肽受体拮抗剂治疗的肝硬化大鼠肝纤维化和血管密度降低，心血管功能和肾功能改善，腹水减少。人类患者的阿片肽水平也显著升高。
阿片肽系统的选择性肝脏激活，以及阿片肽受体阻断导致的纤维化和新生血管生成减少以及心血管和排泄功能改善，表明肝脏阿片肽系统是肝病的一个新治疗靶点。
