Metformin ameliorates TGF-β1-induced osteoblastic differentiation of human aortic valve interstitial cells by inhibiting β-catenin signaling

Osteoblastic differentiation of aortic valve interstitial cells (AVICs) is the central process in the development of calcific aortic valve disease (CAVD). Metformin is a widely used first-line antidiabetic drug, and recently, pleiotropic benefits of metformin beyond hypoglycemia have been reported in the cardiovascular system. Here, we examined the effect of metformin on the osteoblastic differentiation of human AVICs. Our results showed that metformin ameliorated TGF-beta 1-induced production of osteogenic proteins Runx2 and osteopontin as well as calcium deposition in the cultured human AVICs. Experiments using AICAR, Compound C and AMPK alpha siRNA showed that the beneficial effect of metformin on TGF-beta 1-induced osteoblastic differentiation of human AVICs was mediated by AMPK alpha. Moreover, metformin inhibited the TGF-beta 1-induced activation of beta-catenin, and P-catenin siRNA blocked TGF-beta 1-induced osteoblastic differentiation of AVICs. Smad2/3 and JNK were phosphorylated to promote the TGF-beta 1-induced activation of beta-catenin and osteoblastic differentiation of AVICs, and metformin also alleviated TGF-beta 1-induced activation of Smad2/3 and JNK. In conclusion, our results suggest a beneficial effect of metformin based on the prevention of osteoblastic differentiation of human AVICs via inhibition of beta-catenin, which indicates the therapeutic potential of metformin for CAVD. (C) 2018 Elsevier Inc. All rights reserved.