Third Department of Internal Medicine, Nara Medical University, Shijo-cho 840, Kashihara, Nara 634-8522, Japan.
Curr Med Chem. 2012;19(12):1889-98. doi: 10.2174/092986712800099848.
Angiogenesis plays a pivotal role in many pathological processes including chronic liver diseases. Various factors, such as renin-angiotensin-aldosterone system (RAAS), insulin resistance (IR), and reactive oxygen species (ROS) contribute reciprocally to promote angiogenesis. Blockade of RAAS by angiotensin-converting enzyme inhibitor (ACE-I) or angiotensin II (AngII) receptor blocker (ARB) markedly attenuates liver fibrosis and hepatocellular carcinoma (HCC) along with suppression of angiogenesis, IR, and ROS. Aldosterone (Ald), a downstream component of AngII, is also involved in these processes, and a selective Ald blocker (SAB) significantly suppressed the progression of chronic liver diseases. The IR status itself has shown to directly accelerate the progression of chronic liver diseases whereas inhibition of ROS by iron chelator suppressed it through augmentation and inhibition of neovascularization. The combination therapy of ACE-I/ARB/SAB with other clinically used agents, such as interferon, imatinib mesylate, vitamin K, iron chelator, and branched-chain amino acids (BCAA) exerted more potent inhibitory effects on the development of liver fibrosis and HCC than the treatment using a single agent alone. Collectively, the anti-angiogenic treatment targeting RAAS, IR, ROS with clinically available agents may become a new therapeutic strategy against the progression of chronic liver diseases.
血管生成在许多病理过程中起着关键作用，包括慢性肝脏疾病。各种因素，如肾素-血管紧张素-醛固酮系统（RAAS）、胰岛素抵抗（IR）和活性氧物种（ROS），相互促进促进血管生成。血管紧张素转换酶抑制剂（ACE-I）或血管紧张素 II（AngII）受体阻滞剂（ARB）阻断 RAAS 可显著减轻肝纤维化和肝细胞癌（HCC），同时抑制血管生成、IR 和 ROS。醛固酮（Ald）是 AngII 的下游成分，也参与这些过程，选择性 Ald 阻滞剂（SAB）可显著抑制慢性肝病的进展。IR 状态本身已显示可直接加速慢性肝病的进展，而通过增强和抑制新生血管形成，铁螯合剂抑制 ROS 可抑制其进展。ACE-I/ARB/SAB 与其他临床使用的药物（如干扰素、甲磺酸伊马替尼、维生素 K、铁螯合剂和支链氨基酸（BCAA））联合治疗对肝纤维化和 HCC 的发展的抑制作用强于单一药物治疗。总的来说，针对 RAAS、IR 和 ROS 的抗血管生成治疗与临床可用的药物联合应用可能成为治疗慢性肝脏疾病进展的新策略。
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