Abstract 14611: Protease-Activated Receptor 4 Deficiency Impairs Resolution of Inflammation and Predisposes the Heart to Cardiac Rupture After Myocardial Infarction
Introduction: Cardiac rupture is a major lethal complication of acute myocardial infarction (MI). Despite significant advances in reperfusion strategies, mortality from cardiac rupture remains high. Studies suggest that cardiac rupture is accelerated by thrombolytic therapy. However, the mechanisms by which thrombolytic therapy leads to the development of cardiac rupture remains largely unknown.
Hypothesis: In this study, we tested the effect of thrombin protease activated receptor (PAR) 4 deficiency on cardiac rupture and function after MI.
Methods and Results: PAR4 mRNA and protein expression were increased in human ischemic and dilated cardiomyopathy and in response to MI in mice. PAR4 gene deletion in mice protected the heart against acute MI by reducing inflammatory signals and cardiomyocyte apoptosis. However, PAR4-deficient mice showed significantly increased mortality and cardiac rupture rates (3-fold increase vs wild-type mice, P<0.05) along with impaired functional recovery after chronic MI. Pathological evaluation of hearts from PAR4-deficient mice demonstrated a greater infarct expansion (+30% vs wild-type, P<0.05), significantly delayed replacement of injured cardiomyocytes with granulation tissue, and impaired collagen deposition. To understand the mechanisms involved in impaired healing in PAR4 myocardial infarct, we found that PAR4 deficiency attenuated neutrophil apoptosis after MI which resulted in delayed neutrophil accumulation and persistence of pro-inflammatory macrophages. Adoptive transfer of neutrophils derived from wild-type, but not from PAR4-deficient mice, restored inflammation resolution, reduced the incidence of cardiac rupture and mortality and improved cardiac remodeling and function induced after MI in PAR4-deficient mice.
Conclusions: These findings reveal essential roles of PAR4 in neutrophil apoptosis and inflammation resolution during MI and point to PAR4 inhibition as potential therapy that should be limited to the acute phases of ischemic insult and should be avoided for chronic treatment post-MI.
Author Disclosures: M.A. Kolpakov: None. X. Guo: None. B. Hooshdaran: None. K. Rafiq: None. Y.V. Bashkirova: None. L. Vlasenko: None. T. Wang: None. R. Seqqat: None. S.P. Kunapuli: None. S.R. Houser: None. A. Sabri: None.
- © 2016 by American Heart Association, Inc.