Yoshiji Hitoshi, Noguchi Ryuichi, Ikenaka Yasuhide, Kitade Mitsuteru, Kaji Kosuke, Tsujimoto Tatsuhiro, Uemura Masahito, Fukui Hiroshi
Third Department of Internal Medicine, Nara Medical University, Nara, Japan.
Curr Med Chem. 2007;14(26):2749-54. doi: 10.2174/092986707782360169.
The renin-angiotensin system (RAS) is frequently activated in the patients with chronic liver diseases, and recent studies have shown that RAS plays a pivotal role in the progression of chronic liver diseases, i.e., liver fibrosis and hepatocellular carcinoma (HCC). Angiotensin-II (AT-II) reportedly stimulates contractility and proliferation of the activated hepatic stellate cells, and increases the transforming growth factor-beta (TGF-betabeta expression through angiotensin type-I receptors (AT1-R). Many studies have demonstrated that the clinically used angiotensin-converting enzyme inhibitors (ACE-I) and AT1-R blockers (ARB) significantly attenuated the liver fibrosis development in the experimental studies and clinical practice. AT-II also strongly promotes neovascularization, which plays a pivotal role in tumor development. AT-II induces a potent angiogenic factor; namely, the vascular endothelial growth factor (VEGF). It has been reported that ACE-I significantly attenuated the experimental HCC growth and hepatocarcinogenesis along with suppression of neovascularization. The VEGF expression in the tumor was suppressed by ACE-I, too. The combined treatment of ACE-I with other clinically used agents, such as interferon, imatinib mesylate, and vitamin K, shows more potent inhibitory effects on the development of liver fibrosis and HCC. Since RAS inhibitors are widely used in the clinical practice without serious side effects, they may represent a potential new therapeutic strategy against the progression of chronic liver diseases.
肾素-血管紧张素系统（RAS）在慢性肝病患者中经常被激活，最近的研究表明，RAS在慢性肝病（即肝纤维化和肝细胞癌（HCC））的进展中起关键作用。据报道，血管紧张素-II（AT-II）刺激活化的肝星状细胞的收缩性和增殖，并通过I型血管紧张素受体（AT1-R）增加转化生长因子-β（TGF-β）的表达。许多研究表明，临床使用的血管紧张素转换酶抑制剂（ACE-I）和AT1-R阻滞剂（ARB）在实验研究和临床实践中显著减轻了肝纤维化的发展。AT-II还强烈促进新血管形成，这在肿瘤发展中起关键作用。AT-II诱导一种强大的血管生成因子，即血管内皮生长因子（VEGF）。据报道，ACE-I通过抑制新血管形成，显著减轻了实验性HCC的生长和肝癌发生。ACE-I也抑制了肿瘤中的VEGF表达。ACE-I与其他临床使用的药物（如干扰素、甲磺酸伊马替尼和维生素K）联合治疗，对肝纤维化和HCC的发展显示出更强的抑制作用。由于RAS抑制剂在临床实践中广泛使用且无严重副作用，它们可能代表一种针对慢性肝病进展的潜在新治疗策略。
