Abstract 317: Protease Activated Receptor-4 Regulates Post-Infarction Ventricular Remodeling and Cardiac Function
Protease-activated receptor-4 (PAR(4)) is a low affinity thrombin receptor involved in platelet activation and inflammation. PAR-4 is expressed in heart tissue, but its role in the cardiac remodeling known to involve inflammation and leading to heart failure is unknown. In this study, we sought to elucidate the contribution of PAR-4 as a potential mediator of remodeling in human ischemic cardiomyopathy (ICM) and following myocardial infarction (MI) in mice.
Results: Both mRNA and protein expression of PAR-4 were significantly up-regulated in human hearts with ICM compared to heart controls (2.5 and 4.5 fold, p < 0.05, respectively). Immunofluorescence microscopy showed increased PAR-4 expression in cardiomyocytes and coronary smooth muscle cells, but not in fibroblasts or endothelial cells. The role of PAR-4 in the progression of heart failure following myocardial infarction (MI) was studied in PAR-4 KO mice. Left ventricular (LV) ejection fraction and LV wall thickness were similar between PAR-4 KO and wild-type (WT) mice at baseline. After MI, PAR-4 KO mice had significantly lower survival at 1 week compared to WT mice (46 vs 75%, p < 0.05). PAR-4 KO mice also had greater LV dilatation (diastolic dimension 6.14 ± 0.2 vs 4.3 ± 0.1 mm, p < 0.05) and decreased contractility (ejection fraction 17 ± 4 vs 35 ± 5%, p < 0.05) by echocardiography compared to WT mice at 7 days post infarct. Pathological evaluation demonstrated a greater infarct size and thinner LV in PAR-4 KO mice. The rate of apoptosis in LV was significantly greater in PAR-4 KO mice (+4.5-fold) after MI.
Conclusion: These studies show that PAR-4 abundance is increased in human ICM and that lack of PAR-4 exacerbates myocyte loss, fibrosis, ventricular remodeling and functional decline after MI. These results indicate that PAR-4 is a negative regulator of cardiomyocyte death and most likely plays a protective role against progression of congestive heart failure.