Abstract 16584: Bone Morphogenetic Protein 1/Tolloid-Like Metalloproteinase (BMP-1/TLD) is Increased in Heart Failure and Regulates MMP12 and TIMP1 Levels in Cardiomyocytes
Introduction: Myostatin (MSTN) is involved in cardiac remodeling and fibrosis in heart failure (HF), and becomes activated after cleavage by bone morphogenic-1/tolloid (BMP1/TLD) proteinase. We have previously shown that MSTN inhibition prevents cardiac fibrosis via matrix metalloproteinase (MMP)-12 downregulation. The aim of the current study was to delineate the regulatory effects of BMP1 on MSTN, MMP12 and tissue inhibitor of MMPs (TIMP)-1 signaling.
Methods: We measured protein levels in cardiac tissue from patients with dilated cardiomyopathy before and after left ventricular assist device implantation (LVAD) (n=15) and healthy donor hearts (n=4). We also measured the time course of BMP1, MMP12 and TIMP1 activation in heart of mice after myocardial infarction (MI): coronary artery ligation was performed in C57BL/6 mice to induce MI. SHAM and MI mice were sacrificed at different time points (10 min to 2 months) after surgery (n=3/time point). In cardiomyocyte-like AC16 cells, we studied the effect of knock-down of BMP1 by siRNA transfection. After silencing, AC16 cells were treated with different doses of dexamethasone (DEX, 1uM/10uM) or TNFα (1ng/5ng) to induce MSTN upregulation.
Results: BMP1 was upregulated in human HF (150% control, p<0.01) and continued increased after LVAD support (178% control, p<0.01), similarly to the pattern shown by MMP12, while TIMP1 tended to be decreased in HF. In mice, cardiac BMP1 increase was significant 10 min after MI (270% of SHAM) and continued to be elevated after 2 months (234% SHAM), while MMP12 was increased from 2h after MI on. TIMP1 was decreased at all post-MI time points studied (p<0.01). In AC16 cells, treatment with DEX and TNFα resulted in an increase of MSTN, its signaling mediator P-SMAD2,3 and MMP12 (p<0.01). Knockdown of BMP-1 (46% control) decreased MMP12 and increased TIMP1 levels, and prevented DEX and TNF-induced increase in P-SMAD2,3 and MMP12, without affecting DEX and TNFα-induced upregulation of MSTN.
Conclusions: BMP1 is upregulated in chronic human HF and immediately after ischemia in a mouse model of MI. In AC16 cells, BMP1 is necessary for MSTN-induced P-SMAD2,3 activation and regulates MMP12 and TIMP1 levels. These results indicate a vital role of BMP1 in HF remodeling signaling.
Author Disclosures: E. Castillero: None. R. Ji: None. N. Kheysin: None. S. Patel: None. D. Leung: None. S. Hegde: None. J.S. Park: None. S. Stein: None. C. Cuenca: None. H. Akashi: None. C. Wang: None. Z.A. Ali: None. P.C. Colombo: None. H. Sweeney: None. P. Schulze: None. I. George: None.
- © 2016 by American Heart Association, Inc.