Metformin ameliorates TGF-β1–induced osteoblastic differentiation of human aortic valve interstitial cells by inhibiting β-catenin signaling
- Department of Cardiovascular Surgery, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, Hubei 430022 (China)
- Department of Epidemiology and Biostatistics, School of Public Health, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, Hubei 430030 (China)
Highlights: • β-catenin mediates TGF-β–induced osteoblastic differentiation of human AVICs. • Metformin ameliorates osteoblastic differentiation of AVICs by activating AMPKα. • Smad2/3 and JNK signaling mediates TGF-β1–induced activation of β-catenin in AVICs. • Metformin mitigates TGF-β1–induced β-catenin signaling by inhibiting Smad2/3 and JNK. 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-β1–induced production of osteogenic proteins Runx2 and osteopontin as well as calcium deposition in the cultured human AVICs. Experiments using AICAR, Compound C and AMPKα siRNA showed that the beneficial effect of metformin on TGF-β1–induced osteoblastic differentiation of human AVICs was mediated by AMPKα. Moreover, metformin inhibited the TGF-β1–induced activation of β-catenin, and β-catenin siRNA blocked TGF-β1–induced osteoblastic differentiation of AVICs. Smad2/3 and JNK were phosphorylated to promote the TGF-β1–induced activation of β-catenin and osteoblastic differentiation of AVICs, and metformin also alleviated TGF-β1–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 β-catenin, which indicates the therapeutic potential of metformin for CAVD.
- OSTI ID:
- 23125166
- Journal Information:
- Biochemical and Biophysical Research Communications, Journal Name: Biochemical and Biophysical Research Communications Journal Issue: 3 Vol. 500; ISSN 0006-291X; ISSN BBRCA9
- Country of Publication:
- United States
- Language:
- English
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