EphrinA1-Fc Attenuates Ventricular Remodeling and Dysfunction in Chronically Nonreperfused WT but not EphA2-R-M mice

EphrinA1-Fc abolishes acute I/R injury and attenuates nonreperfused cardiac injury 4 days after permanent occlusion in mice. The goal of this study was to assess the capacity of a single intramyocardial administration of ephrinA1-Fc at the time of coronary artery ligation, to determine the degree to...

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Bibliographic Details
Published in:	International journal of molecular sciences Vol. 21; no. 16; p. 5811
Main Authors:	Whitehurst, K'Shylah S, Chan, Victoria A, Estes, Heather K, Valsaraj, Smrithi, Kent, Susan, Sharma, Uma M, Chase, R Christopher, Bhuiyan, Maliha, Virag, Jitka A I
Format:	Journal Article
Language:	English
Published:	Switzerland MDPI AG 13-08-2020 MDPI
Subjects:	Actins - metabolism Animals Attenuation Cardiomyocytes Cells, Cultured Coronary artery Echocardiography Ejection fraction EphA2 EphA2 protein Ephrin-A1 - pharmacology ephrinA1 Fibrosis Gelatinase A Gelatinase B Heart - drug effects Heart - physiopathology Heart diseases Heart failure Hypertrophy Immunoglobulin Fc Fragments - pharmacology Inflammation Kaplan-Meier Estimate Kinases Ligands Matrix metalloproteinases Mice, Transgenic Muscle contraction Myocardial infarction Myocardial Infarction - pathology Myocardial Infarction - physiopathology Myocytes, Cardiac - drug effects Myocytes, Cardiac - pathology Myofibroblasts - metabolism Myofibroblasts - pathology Occlusion Receptor, EphA2 - metabolism remodeling Reperfusion Rodents Smad2 protein Smooth muscle Tissue inhibitor of metalloproteinase 1 Ventricle Ventricular Remodeling - drug effects Western blotting remodeling ephrinA1 fibrosis EphA2 myocardial infarction
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Summary:	EphrinA1-Fc abolishes acute I/R injury and attenuates nonreperfused cardiac injury 4 days after permanent occlusion in mice. The goal of this study was to assess the capacity of a single intramyocardial administration of ephrinA1-Fc at the time of coronary artery ligation, to determine the degree to which early salvage effects translate to reduced adverse remodeling after 4 weeks of nonreperfused myocardial infarction (MI) in wild-type B6 and EphA2-R-M (EphA2 receptor null) mice. At 4 weeks post-MI, echocardiography, histologic and immunohistochemical analyses of B6 mouse hearts were performed. Primary mouse cardiac fibroblasts (FBs) isolated from B6 mice cultured in the presence of low and high dose ephrinA1-Fc, both with and without pro-fibrotic TGF-β stimulation and Western blots, were probed for relative expression of remodeling proteins MMP-2, MMP-9 and TIMP-1, in addition to DDR2 and (p)SMAD2/3/totalSMAD2/3. EphrinA1-Fc preserved a significant degree of contractile function, decreased adverse left ventricular remodeling, attenuated excessive compensatory hypertrophy, and decreased interstitial fibrosis in wild-type (WT) B6 mouse hearts. In contrast, most of these parameters were poorer in ephrinA1-Fc-treated EphA2-R-M mice. Of note, fibrosis was proportionately decreased, implying that other EphA receptor(s) are more important in regulating the pro-fibrotic response. Primary FBs showed disparate alteration of MMP-2, MMP-9 and TIMP-1, as well as DDR2 and p-SMAD2/3/totalSMAD2/3, which indicates that matrix remodeling and cardiac fibrosis in the injured heart are influenced by ephrinA1-Fc. This study demonstrates the capacity of a single administration of ephrinA1-Fc at the onset of injury to attenuate long-term nonreperfused post-MI ventricular remodeling that results in progressive heart failure, and the important role of EphA2 in mitigating the deleterious effects.
Bibliography:	ObjectType-Article-1 SourceType-Scholarly Journals-1 ObjectType-Feature-2 content type line 23
ISSN:	1422-0067 1661-6596 1422-0067
DOI:	10.3390/ijms21165811