Jun-Kun Zhan1, Yan-Jiao Wang1, Yi Wang1, Zhi-Yong Tang1, Pan Tan1, Wu Huang1, You-Shuo Liu2. 1. Department of Geriatrics, Institute of Aging and Geriatrics, The Second Xiangya Hospital, Central South University, Changsha, Hunan 410011, PR China. 2. Department of Geriatrics, Institute of Aging and Geriatrics, The Second Xiangya Hospital, Central South University, Changsha, Hunan 410011, PR China. Electronic address: Liuyoushuo@yeah.net.
Abstract
BACKGROUND: Arterial calcification is a common event in cardiovascular pathogenesis. Osteoblastic differentiation of vascular smooth muscle cells (VSMCs) is the most important cytopathologic foundation of arterial calcification. Glucagon-like peptide-1 (GLP-1) exerts multiple cardioprotective actions beyond insulinotropic effects through GLP-1 receptor (GLP-1R). However, whether GLP-1 regulates osteoblastic differentiation of VSMCs and associated molecular mechanisms has not been clarified. METHODS: The human VSMC differentiation model was established by beta-glycerophosphate (β-GP) induction. The mineralization was measured by Alizarin Red S staining. Protein expression and phosphorylation were detected by Western blot or immunofluorescence. GLP-1R gene expression was silenced by siRNA. RESULTS: The GLP-1 analogue liraglutide dose- and time-dependently inhibited the protein expression of osteoblastic differentiation markers alkaline phosphatase (ALP), osteocalcin (OC), and Runt-related transcription factor 2 (Runx2), phosphorylation of PI3K, Akt, mTOR, and S6K1. Silencing of GLP-1R gene expression by siRNA significantly blocked the effects of liraglutide in ALP protein expression and PI3K/Akt phosphorylation. CONCLUSION: GLP-1 analogue liraglutide attenuates the osteoblastic differentiation and calcification of human VSMCs through its receptor and subsequent activation of PI3K/Akt/mTOR/S6K1 signaling. GLP-1 analogues may be potential agents for the treatment of cardiovascular diseases.
BACKGROUND:Arterial calcification is a common event in cardiovascular pathogenesis. Osteoblastic differentiation of vascular smooth muscle cells (VSMCs) is the most important cytopathologic foundation of arterial calcification. Glucagon-like peptide-1 (GLP-1) exerts multiple cardioprotective actions beyond insulinotropic effects through GLP-1 receptor (GLP-1R). However, whether GLP-1 regulates osteoblastic differentiation of VSMCs and associated molecular mechanisms has not been clarified. METHODS: The human VSMC differentiation model was established by beta-glycerophosphate (β-GP) induction. The mineralization was measured by Alizarin Red S staining. Protein expression and phosphorylation were detected by Western blot or immunofluorescence. GLP-1R gene expression was silenced by siRNA. RESULTS: The GLP-1 analogue liraglutide dose- and time-dependently inhibited the protein expression of osteoblastic differentiation markers alkaline phosphatase (ALP), osteocalcin (OC), and Runt-related transcription factor 2 (Runx2), phosphorylation of PI3K, Akt, mTOR, and S6K1. Silencing of GLP-1R gene expression by siRNA significantly blocked the effects of liraglutide in ALP protein expression and PI3K/Akt phosphorylation. CONCLUSION:GLP-1 analogue liraglutide attenuates the osteoblastic differentiation and calcification of human VSMCs through its receptor and subsequent activation of PI3K/Akt/mTOR/S6K1 signaling. GLP-1 analogues may be potential agents for the treatment of cardiovascular diseases.
Authors: Arvind Ponnusamy; Smeeta Sinha; Gareth D Hyde; Samantha J Borland; Rebecca F Taylor; Emma Pond; Heather J Eyre; Colette A Inkson; Andrew Gilmore; Nick Ashton; Philip A Kalra; Ann E Canfield Journal: PLoS One Date: 2018-04-24 Impact factor: 3.240