Abstract 590: EphrinA1-Fc Attenuates Dysfunction and Fibrosis in Nonreperfused Myocardium at 4 weeks Post-MI in WT B6 but Not EphA2-R Mutant Mice

Abstract

Each year, an estimated 805,000 US citizens have a new or recurrent myocardial infarction (MI), causing over 360,000 deaths. We have previously reported that a single intramyocardial administration of recombinant ephrinA1-Fc, a member of the ephrinA/EphA family of membrane-anchored receptor tyrosine kinases, significantly reduced ischemic injury and remodeling 4 days in nonreperfused WT B6 mice via reduced apoptosis and inflammation and increased autophagic flux. After acute ischemia/reperfusion (30 min I/24hr or 4 days R) in WT B6 mice, ephrinA1-Fc demonstrated anti-inflammatory effects coupled with complete functional preservation due to modulation of cardiomyocyte ultrastructure and metabolism. The goal of this study is to assess the capacity of a single intramyocardial administration of ephrinA1-Fc at the time of permanent coronary artery ligation to maintain the structural and functional salvage effects through the wound healing process to stable scar formation in both B6 and EphA2-R-M (EphA2 receptor null mutant) mice. At 4 weeks post-MI in WT B6 mice, ephrinA1-Fc improved ejection fraction by 11%, attenuated cardiomyocyte hypertrophy by 38%, and decreased interstitial fibrosis by 35%. In contrast, these parameters were not different or worsened in EphA2-R-M mice treated with ephrinA1-Fc, suggesting that this receptor plays an important role in ephrinA1-Fc-mediated mitigation of the deleterious ventricular remodeling caused by permanent coronary artery occlusion. To further investigate the effects of ephrinA1-Fc directly on fibroblast function, isolated primary mouse cardiac fibroblasts were cultured with ephrinA1-Fc both with and without pro-fibrotic TGF-β stimulation to determine the direct effects of ephrinA1-Fc on col I and III production, remodeling mediators MMP-2, MMP-9, and TIMP-1, as well as signaling molecules DDR2 and SMADs2/3 as potential mechanistic pathways involved. The results of these assays are forthcoming. This study demonstrates the potential of a single administration of ephrinA1-Fc to not only attenuate acute ischemic injury but also mitigate pathological accumulation of interstitial fibrosis and remodeling, thereby reducing ventricular stiffening and the resultant progression to heart failure.