Abstract 16843: Protease-Activated Receptor 4 Improves Cardiac Function in Models of Viral, Ischemic and Dilated Cardiomyopathy
Introduction: Cardiomyocytes are a major source of protease-activated receptor 4 (PAR4), in the heart. PAR4 activation facilitates a unique signaling pathway in cardiomyocytes through the epidermal growth factor receptor (EGFR) and src kinase in vitro. EGFR signaling is known to mediate survival of cardiomyocytes and enhance antiviral pathways.
Hypothesis: Here, we investigated if cardiac PAR4 mediates protective effects in three different heart failure models in vivo.
Methods: PAR4-/- mice and wild-type (WT) littermates were compared in models of viral, ischemic or dilated cardiomyopathy. Cardiac injury was analyzed by cardiac troponin I (cTnI) ELISA. Gene expression analyses were performed with ELISA and RT-PCR. Changes in heart dimension and function were evaluated by echocardiography.
Results: PAR4 expression was protective in a coxsackievirus B3 (CVB3) viral cardiomyopathy model. PAR4-/- mice had higher cTnI plasma levels compared to WT mice 8d post infection with 10^5 plaque forming units of CVB3 (cTnI: 3.82±0.97 vs. 1.46±0.35ng/mL; P<0.05) and reduced IFNβ and expression of the IFN-response gene CXCL10. The increased injury at day 8 caused more cardiac remodeling leading to increased left ventricular (LV) dilatation and impaired heart function (fractional shortening [FS]: 27.02±1.45 vs. 32.73±2.16%, P<0.05) 28d after CVB3 infection. In cardiac ischemia/reperfusion injury, PAR4-/- mice exhibited higher plasma levels of cTnI after 30min ischemia and 2h reperfusion compared to WT mice (cTnI: 61.2±7.2 vs. 25.3±2.4 ng/mL; P<0.05). The greater injury in PAR4-/- mice led to more pronounced LV dilatation and impaired LV function after 28d of reperfusion compared to WT mice (FS: 30.92±1.02 vs. 38.55±1.32%; P<0.05). Lastly, in a dilated cardiomyopathy model, PAR4 deficiency was associated with increased cardiac injury (cTnI: 1.03±0.38 vs. 0.13±0.01 ng/mL; P<0.05), increased LV dilatation and more pronounced impairment of LV function (FS: 27.02±1.53 vs. 36.12±1.79%; P<0.05) 5d after administration of doxorubicin (20mg/kg).
Conclusions: Our study indicate that PAR4 mediates protective signaling during viral, ischemic and dilated cardiomyopathy progression in the heart, which may be mediated via EGFR transactivation.
Author Disclosures: S. Antoniak: None. N. Mackman: None.
This research has received full or partial funding support from the American Heart Association
- © 2014 by American Heart Association, Inc.