Possible Involvement of Angiogenesis in Chronic Liver Diseases: Interaction Among Renin-Angiotensin-Aldosterone System, Insulin Resistance and Oxidative Stress

K.      Kaji; H.      Yoshiji; Y.      Ikenaka; R.      Noguchi; Y.      Aihara; Y.      Shirai; A.      Douhara; H.      Fukui

Abstract

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.

Keywords: Aldosterone, Angiogenesis, Angiotensin-II, Hepatic stellate cell, Hepatocellular carcinoma, Insulin resistance, Iron chelator, Liver fibrosis, Nonalcoholic steatohepatitis, Reactive oxygen species, Vascular endothelial growth factor