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Published on: April 15, 2016
Angiotensin II type 1 receptor antagonist prevents hepatic carcinoma in rats with nonalcoholic steatohepatitis
Yosui Tamaki1, Yukiomi Nakade, Taeko Yamauchi
1Division of Metabolism and Biosystemic Science, Department of Internal Medicine, Asahikawa Medical College, Asahikawa, Hokkaido, Japan.
Background:
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.
Methods:
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.
Results:
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-1α (HIF-1α) 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-1α protein and VEGF mRNA.
Conclusions:
These data indicated that telmisartan may prevent hepatocarcinogenesis through the inhibition of hepatic angiogenesis even after liver cirrhosis has been established.
Insights
Telmisartan, an angiotensin II type 1 receptor blocker (ARB), prevents liver cancer (hepatocellular carcinoma) in rats with established liver cirrhosis. It works by inhibiting angiogenesis, the growth of new blood vessels, which fuels tumor development.
Area of Science:
- Hepatology
- Oncology
- Pharmacology
Background:
- Angiotensin II type 1 receptor blockers (ARBs) may reduce liver fibrosis in non-alcoholic steatohepatitis (NASH).
- It remains unclear if ARBs can prevent liver cancer in NASH patients with existing fibrosis.
Purpose of the Study:
- To investigate if telmisartan, an ARB, can prevent liver cancer development in a rat model of NASH with established liver cirrhosis.
Main Methods:
- Rats were fed a choline-deficient, L-amino acid-defined (CDAA) diet for 48 weeks.
- Telmisartan was administered during the last 24 weeks of the CDAA diet to assess its effects on liver histology and angiogenesis markers.
Main Results:
- The CDAA diet induced liver cirrhosis and hepatocellular carcinoma (HCC) in 54.6% of rats.
- Telmisartan treatment inhibited fibrosis, preneoplastic lesions, and prevented HCC development.
- Telmisartan reduced levels of hypoxia-inducible factor-1α (HIF-1α) and vascular endothelial growth factor (VEGF) mRNA, key angiogenesis factors.
Conclusions:
- Telmisartan demonstrates potential in preventing liver cancer even after liver cirrhosis is established.
- Inhibition of hepatic angiogenesis is a likely mechanism by which telmisartan exerts its anti-cancer effects in NASH.
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