Activation of AMP-activated Protein Kinase by Metformin Inhibits Dedifferentiation of Platelet-derived Growth Factor-BB-induced Vascular Smooth Muscle Cells to Improve Arterial Remodeling in Cirrhotic Portal Hypertension
Abstract
BACKGROUND & AIMS: Portal hypertension (PHT) is the potentially deadly complication of liver cirrhosis. Intrahepatic vascular resistance and the splanchnic hyperdynamic circulation are 2 principal driving factors contributing to the maintenance and exacerbation of PHT. However, in the advanced stages of cirrhosis, the fibrotic process in the liver becomes irreversible, leading to persistent and intractable increases in intrahepatic vascular resistance. Arterial remodeling emerges as a crucial mechanism driving the hyperdynamic splanchnic circulation. Therefore, ameliorating the hyperdynamic splanchnic circulation has become an indispensable component of PHT therapeutic strategies.
METHODS: Liver cirrhosis with PHT was induced in the rats by common bile duct ligation (BDL). Based on the transcriptomic sequencing of the mesenteric arteries, we investigated the effects and mechanisms of metformin on the arterial remodeling at different stages of cirrhosis. We further validated potential molecular mechanisms through in vitro experiments using the A7r5 smooth muscle cell line and primary vascular smooth muscle cells (VSMCs).
RESULTS: Our findings revealed the beneficial effects of metformin on liver cirrhosis and PHT in rats following BDL for 4 and 6 weeks. Metformin was observed to ameliorate PHT and splanchnic hyperdynamic circulation in BDL rats, even in the advanced stages of liver cirrhosis. This effect was evidenced by reduced portal pressure and cardiac output, decreased…
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