Angiotensin II type 1 receptor antagonist prevents hepatic carcinoma in rats with nonalcoholic steatohepatitis
Angiotensin II type 1 receptor antagonist prevents hepatic carcinoma in rats with nonalcoholic steatohepatitis
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DOI：
10.1007/s00535-012-0651-7
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发表时间：
2013-04-01
影响因子：
6.3
通讯作者：
Yoneda, Masashi
中科院分区：
文献类型：
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作者：
Tamaki, Yosui;Nakade, Yukiomi;Yoneda, Masashi
据报道，血管紧张素II 1型受体阻滞剂（ARB）可减轻非酒精性脂肪性肝炎（NASH）的肝纤维化。雄性Wistar大鼠用胆碱缺乏、l-氨基酸定义（CDAA）饲料喂养24周，然后用含替米沙坦（2 mg/kg/天）、一种新型ARB或溶媒的CDAA饲料喂养24周。观察肝组织学变化及血管生成相关基因和蛋白的表达。48周的CDAA饮食加重了肝硬化，并在54.6%的大鼠中发展为肝细胞癌（HCC），同时伴有缺氧诱导因子-1 α（HIF-1 α）蛋白和血管内皮生长因子（VEGF）mRNA的增加，这是肝脏中有效的血管生成因子。替米沙坦可抑制肝纤维化和癌前病变，并沿着诱导HIF-1 α蛋白和VEGF mRNA的降低，从而阻止HCC的发展。这些数据表明，即使在肝硬化已经建立后，替米沙坦也可能通过抑制肝血管生成来预防肝癌的发生。
Angiotensin II type 1 receptor blockers (ARBs) have been reported to attenuate hepatic fibrosis in non-alcoholic steatohepatitis (NASH). However, it is uncertain whether ARBs prevent hepatocarcinogenesis in NASH even after hepatic fibrosis has developed.Male Wistar rats were fed with a choline-deficient, l-amino acid-defined (CDAA) diet for 24 weeks, and then fed with the CDAA diet with telmisartan (2 mg/kg/day), a novel ARB, or vehicle for another 24 weeks. The liver histology and the expression of genes and proteins related to angiogenesis were investigated.The 24-week CDAA diet induced liver cirrhosis. The 48-week CDAA diet exacerbated liver cirrhosis, and developed hepatocellular carcinoma (HCC) in 54.6 % of the rats concurrently with increases of hypoxia-inducible factor-1 alpha (HIF-1 alpha) protein and vascular endothelial growth factor (VEGF) mRNA, which are potent angiogenic factors in the liver. Telmisartan inhibited hepatic fibrosis and preneoplastic lesions and prevented the development of HCC along with inducing decreases in HIF-1 alpha protein and VEGF mRNA.These data indicated that telmisartan may prevent hepatocarcinogenesis through the inhibition of hepatic angiogenesis even after liver cirrhosis has been established.