Abstract 311: Inhibition Of Matrix Metalloproteinase-13 Dependent Protease-activated Receptor-1 Activation Attenuates Fibrotic Signaling
Heart failure (HF) is the leading cause of morbidity and mortality in the United States and is characterized by progressive myocardial fibrosis, pathologic remodeling and deteriorating cardiac function. Cardiac fibroblasts (CF) are largely responsible for the secretion of ECM proteins as well as cytokines and growth factors in the heart. Upon injury or pathologic stimulation, CF transition to a myofibroblast phenotype, leading to excess production of ECM proteins and pro-inflammatory cytokines. Previous studies in our lab have indicated a role for protease-activated receptor-1 (PAR-1), the most highly expressed GPCR on CF, in pathologic cardiac remodeling. In particular, we reported the novel cleavage of PAR-1 via matrix metalloproteinase-13 (MMP-13) and cardioprotective effects of MMP-13 inhibition in an acute model of HF. Therefore, we hypothesize that MMP-13 plays an important role in cardiac remodeling through activation of PAR-1, particularly in the pathologic transition of CF to myofibroblasts.
To investigate this hypothesis, RNA was collected from hearts of mice infused with isoproterenol (ISO) for 7 days and concurrently treated with a specific MMP-13 inhibitor, WAY170523, or vehicle. To evaluate the effect of WAY170523, we used qRT-PCR to measure changes in the expression of fibrotic markers, COL1a1, COL3a1, and TGF-β. Inhibition of MMP-13 with WAY170523 attenuated expression of these genes compared to vehicle treated animals.
We previously reported that stimulation of CF and cardiomyocytes with MMP-13 induces phosphorylation of ERK1/2, a member of the MAPK family known to play a role in cardiac hypertrophy, and treatment with a direct PAR-1 antagonist decreased the activation of ERK1/2. We have found that ERK1/2 phosphorylation is directly attenuated following inhibition of MMP-13 with WAY170523.
Overall, these data suggest a role for MMP-13 dependent PAR-1 activation in pathologic myofibroblast transition and a potential therapeutic role for MMP-13 inhibition, possibly through its inhibition of ERK1/2 phosphorylation. Treatment with WAY170523 also attenuates markers of fibrosis in vivo, indicating a potential salutary role for MMP-13 inhibition in the treatment of HF.
Author Disclosures: A.E. Dixon: None F. Jaffre: None N. Mackman: None B.C. Blaxall: None.
- © 2014 by American Heart Association, Inc.