Xin-Sheng Deng1, Xianzhong Meng2, Fei Li2, Neil Venardos2, David Fullerton2, James Jaggers3. 1. Cardiothoracic Surgery, University of Colorado, Children's Hospital Colorado, Aurora, Colorado; Cardiothoracic Surgery, University of Colorado Anschutz Medical Campus, Aurora, Colorado. 2. Cardiothoracic Surgery, University of Colorado Anschutz Medical Campus, Aurora, Colorado. 3. Cardiothoracic Surgery, University of Colorado, Children's Hospital Colorado, Aurora, Colorado; Cardiothoracic Surgery, University of Colorado Anschutz Medical Campus, Aurora, Colorado. Electronic address: James.Jaggers@childrenscolorado.org.
Abstract
BACKGROUND: Calcific aortic valve disease (CAVD) is an age-related and slowly progressive valvular disorder. Overexpression of matrix metalloproteinase 12 (MMP-12) has been found in atherosclerosis, stiffed vascular tissue, and calcified aortic valves. We hypothesized that MMP-12 may induce the pro-osteogenic responses in human aortic valve interstitial cells (AVICs). METHODS: Human AVICs were isolated from normal and calcified aortic valves. Cells were treated with MMP-12. The pro-osteogenic marker Runt-related transcription factor 2 (RUNX-2), bone morphogenetic protein 2 (BMP-2), and alkaline phosphatase (ALP), as well as MMP-12-associated signaling molecules, were analyzed. RESULTS: Human calcified aortic valves expressed significantly higher MMP-12 than normal human aortic valves. MMP-12-induced the expression of RUNX-2, BMP-2, ALP, and calcium deposit formation. Suppression of MMP-12 by its inhibitor decreased the expression of RUNX-2, BMP-2, and ALP. MMP-12-induced osteogenic responses were associated with higher levels of phosphorylation of p38 mitogen-activated protein kinases (MAPK), low density lipoprotein-related protein 6 (LRP-6), and β-catenin signaling molecules. Calcified aortic valves exhibited markedly higher levels of LRP-6 and β-catenin levels. Inhibition of either p38 MAPK or LRP-6 attenuated MMP-12-induced expression of RUNX-2, BMP-2, and ALP. Suppression of p38 MAPK abrogated MMP-12-induced activation of LRP-6 and β-catenin signaling pathways. CONCLUSIONS: MMP-12 induces pro-osteogenic responses in AVICs by activation of p38 MAPK-mediated LRP-6 and β-catenin signaling pathways. The study revealed that the potential role of MMP-12 in the pathogenesis of CAVD and therapeutically targeting MMP-12 may suppress the development of CAVD.
BACKGROUND:Calcific aortic valve disease (CAVD) is an age-related and slowly progressive valvular disorder. Overexpression of matrix metalloproteinase 12 (MMP-12) has been found in atherosclerosis, stiffed vascular tissue, and calcified aortic valves. We hypothesized that MMP-12 may induce the pro-osteogenic responses in human aortic valve interstitial cells (AVICs). METHODS:Human AVICs were isolated from normal and calcified aortic valves. Cells were treated with MMP-12. The pro-osteogenic marker Runt-related transcription factor 2 (RUNX-2), bone morphogenetic protein 2 (BMP-2), and alkaline phosphatase (ALP), as well as MMP-12-associated signaling molecules, were analyzed. RESULTS:Human calcified aortic valves expressed significantly higher MMP-12 than normal human aortic valves. MMP-12-induced the expression of RUNX-2, BMP-2, ALP, and calcium deposit formation. Suppression of MMP-12 by its inhibitor decreased the expression of RUNX-2, BMP-2, and ALP. MMP-12-induced osteogenic responses were associated with higher levels of phosphorylation of p38 mitogen-activated protein kinases (MAPK), low density lipoprotein-related protein 6 (LRP-6), and β-catenin signaling molecules. Calcified aortic valves exhibited markedly higher levels of LRP-6 and β-catenin levels. Inhibition of either p38 MAPK or LRP-6 attenuated MMP-12-induced expression of RUNX-2, BMP-2, and ALP. Suppression of p38 MAPK abrogated MMP-12-induced activation of LRP-6 and β-catenin signaling pathways. CONCLUSIONS:MMP-12 induces pro-osteogenic responses in AVICs by activation of p38 MAPK-mediated LRP-6 and β-catenin signaling pathways. The study revealed that the potential role of MMP-12 in the pathogenesis of CAVD and therapeutically targeting MMP-12 may suppress the development of CAVD.
Authors: Aeron Small; Daniel Kiss; Jay Giri; Saif Anwaruddin; Hasan Siddiqi; Marie Guerraty; Julio A Chirinos; Giovanni Ferrari; Daniel J Rader Journal: Arterioscler Thromb Vasc Biol Date: 2017-02-02 Impact factor: 8.311
Authors: Brian R Lindman; Marie-Annick Clavel; Patrick Mathieu; Bernard Iung; Patrizio Lancellotti; Catherine M Otto; Philippe Pibarot Journal: Nat Rev Dis Primers Date: 2016-03-03 Impact factor: 52.329
Authors: Shu-Lin Liu; Yong Ho Bae; Christopher Yu; James Monslow; Elizabeth A Hawthorne; Paola Castagnino; Emanuela Branchetti; Giovanni Ferrari; Scott M Damrauer; Ellen Puré; Richard K Assoian Journal: Sci Rep Date: 2015-11-26 Impact factor: 4.379