{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,5,15]],"date-time":"2026-05-15T05:20:31Z","timestamp":1778822431867,"version":"3.51.4"},"reference-count":49,"publisher":"MDPI AG","issue":"16","license":[{"start":{"date-parts":[[2020,8,13]],"date-time":"2020-08-13T00:00:00Z","timestamp":1597276800000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"DOI":"10.13039\/100000050","name":"National Heart, Lung, and Blood Institute","doi-asserted-by":"publisher","award":["1RH15HL124483-01A1"],"award-info":[{"award-number":["1RH15HL124483-01A1"]}],"id":[{"id":"10.13039\/100000050","id-type":"DOI","asserted-by":"publisher"}]}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["IJMS"],"abstract":"<jats:p>Background: 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. Methods: 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-\u03b2 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. Results: 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. Conclusion: 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.<\/jats:p>","DOI":"10.3390\/ijms21165811","type":"journal-article","created":{"date-parts":[[2020,8,13]],"date-time":"2020-08-13T09:23:44Z","timestamp":1597310624000},"page":"5811","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":7,"title":["EphrinA1-Fc Attenuates Ventricular Remodeling and Dysfunction in Chronically Nonreperfused WT but not EphA2-R-M mice"],"prefix":"10.3390","volume":"21","author":[{"given":"K\u2019Shylah S.","family":"Whitehurst","sequence":"first","affiliation":[{"name":"Department of Physiology, Brody School of Medicine, East Carolina University, Greenville, NC 27834, USA"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Victoria A.","family":"Chan","sequence":"additional","affiliation":[{"name":"Department of Physiology, Brody School of Medicine, East Carolina University, Greenville, NC 27834, USA"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Heather K.","family":"Estes","sequence":"additional","affiliation":[{"name":"Department of Physiology, Brody School of Medicine, East Carolina University, Greenville, NC 27834, USA"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Smrithi","family":"Valsaraj","sequence":"additional","affiliation":[{"name":"Department of Physiology, Brody School of Medicine, East Carolina University, Greenville, NC 27834, USA"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Susan","family":"Kent","sequence":"additional","affiliation":[{"name":"Department of Physiology, Brody School of Medicine, East Carolina University, Greenville, NC 27834, USA"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Uma M.","family":"Sharma","sequence":"additional","affiliation":[{"name":"Department of Physiology, Brody School of Medicine, East Carolina University, Greenville, NC 27834, USA"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"R. Christopher","family":"Chase","sequence":"additional","affiliation":[{"name":"Department of Physiology, Brody School of Medicine, East Carolina University, Greenville, NC 27834, USA"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Maliha","family":"Bhuiyan","sequence":"additional","affiliation":[{"name":"Department of Physiology, Brody School of Medicine, East Carolina University, Greenville, NC 27834, USA"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-3321-9861","authenticated-orcid":false,"given":"Jitka A. I.","family":"Virag","sequence":"additional","affiliation":[{"name":"Department of Physiology, Brody School of Medicine, East Carolina University, Greenville, NC 27834, USA"}],"role":[{"role":"author","vocabulary":"crossref"}]}],"member":"1968","published-online":{"date-parts":[[2020,8,13]]},"reference":[{"key":"ref_1","doi-asserted-by":"crossref","first-page":"38","DOI":"10.1016\/j.cell.2008.03.011","article-title":"Eph-ephrin bidirectional signaling in physiology and disease","volume":"133","author":"Pasquale","year":"2008","journal-title":"Cell"},{"key":"ref_2","doi-asserted-by":"crossref","first-page":"475","DOI":"10.1038\/nrm856","article-title":"Mechanisms and functions of Eph and ephrin signalling","volume":"3","author":"Kullander","year":"2002","journal-title":"Nat. Rev. Mol. Cell Biol."},{"key":"ref_3","doi-asserted-by":"crossref","first-page":"7011","DOI":"10.1038\/sj.onc.1205679","article-title":"Soluble Eph A receptors inhibit tumor angiogenesis and progression in vivo","volume":"21","author":"Brantley","year":"2002","journal-title":"Oncogene"},{"key":"ref_4","doi-asserted-by":"crossref","first-page":"165","DOI":"10.2217\/fon.09.146","article-title":"Ephrin expression and function in cancer","volume":"6","author":"McCarron","year":"2010","journal-title":"Future Oncol."},{"key":"ref_5","doi-asserted-by":"crossref","first-page":"a009159","DOI":"10.1101\/cshperspect.a009159","article-title":"Eph receptor signaling and ephrins","volume":"5","author":"Lisabeth","year":"2013","journal-title":"Cold Spring Harb. Perspect. Biol."},{"key":"ref_6","doi-asserted-by":"crossref","first-page":"567","DOI":"10.1126\/science.7536959","article-title":"Role of B61, the ligand for the Eck receptor tyrosine kinase, in TNF-alpha-induced angiogenesis","volume":"268","author":"Pandey","year":"1995","journal-title":"Science"},{"key":"ref_7","doi-asserted-by":"crossref","first-page":"75","DOI":"10.1016\/S1359-6101(01)00031-4","article-title":"The ephrins and Eph receptors in angiogenesis","volume":"13","author":"Cheng","year":"2002","journal-title":"Cytokine Growth Factor Rev."},{"key":"ref_8","doi-asserted-by":"crossref","first-page":"3431","DOI":"10.2174\/1381612043383160","article-title":"Eph receptor tyrosine kinases in tumor and tumor microenvironment","volume":"10","author":"Schmidt","year":"2004","journal-title":"Curr. Pharm. Des."},{"key":"ref_9","doi-asserted-by":"crossref","first-page":"10315","DOI":"10.1158\/0008-5472.CAN-06-1560","article-title":"Ephrin-A1 facilitates mammary tumor metastasis through an angiogenesis-dependent mechanism mediated by EphA receptor and vascular endothelial growth factor in mice","volume":"66","author":"Fang","year":"2006","journal-title":"Cancer Res."},{"key":"ref_10","doi-asserted-by":"crossref","first-page":"109","DOI":"10.1016\/j.semcdb.2011.10.019","article-title":"Ephs and ephrins in cancer: Ephrin-A1 signalling","volume":"23","author":"Beauchamp","year":"2011","journal-title":"Semin. Cell Dev. Biol."},{"key":"ref_11","doi-asserted-by":"crossref","first-page":"2388","DOI":"10.2353\/ajpath.2009.080949","article-title":"Capillary defects and exaggerated inflammatory response in the airways of EphA2-deficient mice","volume":"174","author":"Okazaki","year":"2009","journal-title":"Am. J. Pathol."},{"key":"ref_12","doi-asserted-by":"crossref","first-page":"42","DOI":"10.1016\/j.phrs.2012.10.008","article-title":"Ephs and ephrins resurface in inflammation, immunity, and atherosclerosis","volume":"67","author":"Funk","year":"2013","journal-title":"Pharmacol. Res."},{"key":"ref_13","doi-asserted-by":"crossref","first-page":"1493","DOI":"10.1016\/j.ajpath.2012.06.043","article-title":"Eph\/Ephrin signaling in injury and inflammation","volume":"181","author":"Coulthard","year":"2012","journal-title":"Am. J. Pathol."},{"key":"ref_14","doi-asserted-by":"crossref","first-page":"389","DOI":"10.1080\/15216540600756004","article-title":"Putative dual role of ephrin-Eph receptor interactions in inflammation","volume":"58","author":"Ivanov","year":"2006","journal-title":"IUBMB Life"},{"key":"ref_15","doi-asserted-by":"crossref","first-page":"1563","DOI":"10.1111\/j.1476-5381.2012.02117.x","article-title":"Regulation of apoptosis in HL-1 cardiomyocytes by phosphorylation of the receptor tyrosine kinase EphA2 and protection by lithocholic acid","volume":"167","author":"Jehle","year":"2012","journal-title":"Br. J. Pharmacol."},{"key":"ref_16","doi-asserted-by":"crossref","unstructured":"DuSablon, A., Parks, J., Whitehurst, K., Estes, H., Chase, R., Vlahos, E., Sharma, U., Wert, D., and Virag, J. (2017). EphrinA1-Fc attenuates myocardial ischemia\/reperfusion injury in mice. PLoS ONE, 12.","DOI":"10.1371\/journal.pone.0189307"},{"key":"ref_17","doi-asserted-by":"crossref","first-page":"1725","DOI":"10.1113\/jphysiol.2010.202366","article-title":"Intramyocardial administration of chimeric ephrinA1-Fc promotes tissue salvage following myocardial infarction in mice","volume":"589 Pt 7","author":"Dries","year":"2011","journal-title":"J. Physiol."},{"key":"ref_18","doi-asserted-by":"crossref","first-page":"117053","DOI":"10.1016\/j.lfs.2019.117053","article-title":"Intracardiac administration of ephrinA1-Fc preserves mitochondrial bioenergetics during acute ischemia\/reperfusion injury","volume":"239","author":"Torres","year":"2019","journal-title":"Life Sci."},{"key":"ref_19","first-page":"132","article-title":"Deletion of the EphA2 receptor exacerbates myocardial injury and the progression of ischemic cardiomyopathy","volume":"5","author":"Griffin","year":"2014","journal-title":"Front. Physiol."},{"key":"ref_20","doi-asserted-by":"crossref","first-page":"738","DOI":"10.1016\/j.mehy.2013.02.024","article-title":"Ephrin-Eph signaling as a potential therapeutic target for the treatment of myocardial infarction","volume":"80","author":"Griffin","year":"2013","journal-title":"Med. Hypotheses"},{"key":"ref_21","doi-asserted-by":"crossref","first-page":"A590","DOI":"10.1161\/res.125.suppl_1.590","article-title":"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","volume":"125","author":"Whitehurst","year":"2019","journal-title":"Circ. Res."},{"key":"ref_22","doi-asserted-by":"crossref","first-page":"155","DOI":"10.1136\/heartjnl-2013-304289","article-title":"Infarct size reduction in acute myocardial infarction","volume":"101","author":"McAlindon","year":"2015","journal-title":"Heart"},{"key":"ref_23","doi-asserted-by":"crossref","unstructured":"Thundyil, J., Manzanero, S., Pavlovski, D., Cully, T.R., Lok, K.Z., Widiapradja, A., Chunduri, P., Jo, D.G., Naruse, C., and Asano, M. (2013). Evidence that the EphA2 receptor exacerbates ischemic brain injury. PLoS ONE, 8.","DOI":"10.1371\/journal.pone.0053528"},{"key":"ref_24","doi-asserted-by":"crossref","first-page":"F960","DOI":"10.1152\/ajprenal.00020.2006","article-title":"Upregulation of EphA2 during in vivo and in vitro renal ischemia-reperfusion injury: Role of Src kinases","volume":"291","author":"Baldwin","year":"2006","journal-title":"Am. J. Physiol. Ren. Physiol."},{"key":"ref_25","doi-asserted-by":"crossref","first-page":"272","DOI":"10.1002\/ejhf.1406","article-title":"Towards better definition, quantification and treatment of fibrosis in heart failure. A scientific roadmap by the Committee of Translational Research of the Heart Failure Association (HFA) of the European Society of Cardiology","volume":"21","author":"Bauersachs","year":"2019","journal-title":"Eur. J. Heart Fail."},{"key":"ref_26","doi-asserted-by":"crossref","first-page":"699","DOI":"10.1016\/j.yjmcc.2005.07.008","article-title":"Altered fibroblast function following myocardial infarction","volume":"39","author":"Squires","year":"2005","journal-title":"J. Mol. Cell. Cardiol."},{"key":"ref_27","doi-asserted-by":"crossref","first-page":"247","DOI":"10.1016\/j.matbio.2015.03.005","article-title":"The role of TIMPs in regulation of extracellular matrix proteolysis","volume":"44\u201346","author":"Arpino","year":"2015","journal-title":"Matrix Biol."},{"key":"ref_28","doi-asserted-by":"crossref","first-page":"214","DOI":"10.1016\/S0008-6363(00)00003-1","article-title":"Interplay of matrix metalloproteinases, tissue inhibitors of metalloproteinases and their regulators in cardiac matrix remodeling","volume":"46","author":"Li","year":"2000","journal-title":"Cardiovasc. Res."},{"key":"ref_29","doi-asserted-by":"crossref","first-page":"1907","DOI":"10.1089\/ars.2006.8.1907","article-title":"The mechanistic basis of infarct healing","volume":"8","author":"Frangogiannis","year":"2006","journal-title":"Antioxid. Redox Signal."},{"key":"ref_30","doi-asserted-by":"crossref","first-page":"3253","DOI":"10.1128\/MCB.06791-11","article-title":"EphrinA1 is released in three forms from cancer cells by matrix metalloproteases","volume":"32","author":"Beauchamp","year":"2012","journal-title":"Mol. Cell. Biol."},{"key":"ref_31","doi-asserted-by":"crossref","first-page":"1164","DOI":"10.1161\/CIRCRESAHA.109.209809","article-title":"Cardiac fibroblast: The renaissance cell","volume":"105","author":"Souders","year":"2009","journal-title":"Circ. Res."},{"key":"ref_32","doi-asserted-by":"crossref","first-page":"614","DOI":"10.1161\/01.HYP.0000175811.79863.e2","article-title":"Regulation of discoidin domain receptor 2 by cyclic mechanical stretch in cultured rat vascular smooth muscle cells","volume":"46","author":"Shyu","year":"2005","journal-title":"Hypertension"},{"key":"ref_33","doi-asserted-by":"crossref","first-page":"3606","DOI":"10.1074\/jbc.M107571200","article-title":"Discoidin domain receptor 2 regulates fibroblast proliferation and migration through the extracellular matrix in association with transcriptional activation of matrix metalloproteinase-2","volume":"277","author":"Olaso","year":"2002","journal-title":"J. Biol. Chem."},{"key":"ref_34","doi-asserted-by":"crossref","first-page":"3770","DOI":"10.1172\/JCI94753","article-title":"Fibroblast-specific TGF-beta-Smad2\/3 signaling underlies cardiac fibrosis","volume":"127","author":"Khalil","year":"2017","journal-title":"J. Clin. Investig."},{"key":"ref_35","doi-asserted-by":"crossref","first-page":"2017","DOI":"10.1016\/j.cellsig.2013.06.001","article-title":"Transforming growth factor-beta signalling: Role and consequences of Smad linker region phosphorylation","volume":"25","author":"Kamato","year":"2013","journal-title":"Cell. Signal."},{"key":"ref_36","doi-asserted-by":"crossref","first-page":"549","DOI":"10.1007\/s00018-013-1349-6","article-title":"The pathogenesis of cardiac fibrosis","volume":"71","author":"Kong","year":"2014","journal-title":"Cell. Mol. Life Sci."},{"key":"ref_37","doi-asserted-by":"crossref","first-page":"3129","DOI":"10.1161\/01.CIR.0000147180.87553.79","article-title":"Increased myocardial collagen content in transgenic rats overexpressing cardiac angiotensin-converting enzyme is related to enhanced breakdown of N-acetyl-Ser-Asp-Lys-Pro and increased phosphorylation of Smad2\/3","volume":"110","author":"Pokharel","year":"2004","journal-title":"Circulation"},{"key":"ref_38","doi-asserted-by":"crossref","first-page":"60","DOI":"10.1007\/s00395-007-0689-5","article-title":"Transforming growth factor-beta receptor antagonism attenuates myocardial fibrosis in mice with cardiac-restricted overexpression of tumor necrosis factor","volume":"103","author":"Sakata","year":"2008","journal-title":"Basic Res. Cardiol."},{"key":"ref_39","doi-asserted-by":"crossref","first-page":"109","DOI":"10.1016\/j.yjmcc.2017.07.011","article-title":"Entanglement of GSK-3beta, beta-catenin and TGF-beta1 signaling network to regulate myocardial fibrosis","volume":"110","author":"Guo","year":"2017","journal-title":"J. Mol. Cell. Cardiol."},{"key":"ref_40","doi-asserted-by":"crossref","unstructured":"Horton, J.L., and Virag, J. (2019). Use of Multifactorial Treatments to Address the Challenge of Translating Experimental Myocardial Infarct Reduction Strategies. Int. J. Mol. Sci., 20.","DOI":"10.3390\/ijms20061449"},{"key":"ref_41","doi-asserted-by":"crossref","first-page":"89","DOI":"10.1016\/j.jacc.2018.09.086","article-title":"Multitarget strategies to reduce myocardial ischemia\/reperfusion injury: JACC review topic of the week","volume":"73","author":"Davidson","year":"2019","journal-title":"J. Am. Coll. Cardiol."},{"key":"ref_42","doi-asserted-by":"crossref","first-page":"1033","DOI":"10.1083\/jcb.201104037","article-title":"Eph receptor function is modulated by heterooligomerization of A and B type Eph receptors","volume":"195","author":"Janes","year":"2011","journal-title":"J. Cell Biol."},{"key":"ref_43","doi-asserted-by":"crossref","first-page":"114","DOI":"10.1186\/s12933-014-0114-y","article-title":"EphA2-receptor deficiency exacerbates myocardial infarction and reduces survival in hyperglycemic mice","volume":"13","author":"DuSablon","year":"2014","journal-title":"Cardiovasc. Diabetol."},{"key":"ref_44","first-page":"e2581","article-title":"Coronary Artery Ligation and Intramyocardial Injection in a Murine Model of Infarction","volume":"7","author":"Virag","year":"2011","journal-title":"J. Vis. Exp."},{"key":"ref_45","first-page":"H1967","article-title":"Echocardiographic assessment of cardiac function in conscious and anesthetized mice","volume":"277","author":"Yang","year":"1999","journal-title":"Am. J. Physiol."},{"key":"ref_46","doi-asserted-by":"crossref","first-page":"167","DOI":"10.1093\/ejechocard\/jer021","article-title":"Current and evolving echocardiographic techniques for the quantitative evaluation of cardiac mechanics: ASE\/EAE consensus statement on methodology and indications endorsed by the Japanese Society of Echocardiography","volume":"12","author":"Lang","year":"2011","journal-title":"Eur. J. Echocardiogr."},{"key":"ref_47","doi-asserted-by":"crossref","first-page":"1431","DOI":"10.2353\/ajpath.2007.070003","article-title":"Fibroblast growth factor-2 regulates myocardial infarct repair: Effects on cell proliferation, scar contraction, and ventricular function","volume":"171","author":"Virag","year":"2007","journal-title":"Am. J. Pathol."},{"key":"ref_48","doi-asserted-by":"crossref","first-page":"24043","DOI":"10.1074\/jbc.M114.554766","article-title":"Transactivation of the receptor-tyrosine kinase ephrin receptor A2 is required for the low molecular weight hyaluronan-mediated angiogenesis that is implicated in tumor progression","volume":"289","author":"Lennon","year":"2014","journal-title":"J. Biol. Chem."},{"key":"ref_49","doi-asserted-by":"crossref","first-page":"2528","DOI":"10.1089\/ten.tea.2012.0094","article-title":"Response of fibroblasts to transforming growth factor-beta1 on two-dimensional and in three-dimensional hyaluronan hydrogels","volume":"18","author":"Chen","year":"2012","journal-title":"Tissue Eng. Part A"}],"container-title":["International Journal of Molecular Sciences"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/www.mdpi.com\/1422-0067\/21\/16\/5811\/pdf","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2025,10,11]],"date-time":"2025-10-11T10:00:07Z","timestamp":1760176807000},"score":1,"resource":{"primary":{"URL":"https:\/\/www.mdpi.com\/1422-0067\/21\/16\/5811"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2020,8,13]]},"references-count":49,"journal-issue":{"issue":"16","published-online":{"date-parts":[[2020,8]]}},"alternative-id":["ijms21165811"],"URL":"https:\/\/doi.org\/10.3390\/ijms21165811","relation":{},"ISSN":["1422-0067"],"issn-type":[{"value":"1422-0067","type":"electronic"}],"subject":[],"published":{"date-parts":[[2020,8,13]]}}}