EphA2-receptor deficiency exacerbates myocardial infarction and reduces survival in hyperglycemic mice

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dc.contributor.authorDuSablon, Augustin
dc.contributor.authorKent, Susan D.
dc.contributor.authorCoburn, Anita
dc.contributor.authorVirag, Jitka A. I.
dc.date.accessioned2016-06-28T13:46:20Z
dc.date.available2016-06-28T13:46:20Z
dc.date.issued2014-08
dc.description.abstractBackground We have previously shown that EphrinA1/EphA expression profile changes in response to myocardial infarction (MI), exogenous EphrinA1-Fc administration following MI positively influences wound healing, and that deletion of the EphA2 Receptor (EphA2-R) exacerbates injury and remodeling. To determine whether or not ephrinA1-Fc would be of therapeutic value in the hyperglycemic infarcted heart, it is critical to evaluate how ephrinA1/EphA signaling changes in the hyperglycemic myocardium in response to MI. Methods Streptozotocin (STZ)-induced hyperglycemia in wild type (WT) and EphA2-receptor mutant (EphA2-R-M) mice was initiated by an intraperitoneal injection of STZ (150 mg/kg) 10 days before surgery. MI was induced by permanent ligation of the left anterior descending coronary artery and analyses were performed at 4 days post-MI. ANOVAs with Student-Newman Keuls multiple comparison post-hoc analysis illustrated which groups were significantly different, with significance of at least pā€‰<ā€‰0.05. Results Both WT and EphA2-R-M mice responded adversely to STZ, but only hyperglycemic EphA2-R-M mice had lower ejection fraction (EF) and fractional shortening (FS). At 4 days post-MI, we observed greater post-MI mortality in EphA2-R-M mice compared with WT and this was greater still in the EphA2-R-M hyperglycemic mice. Although infarct size was greater in hyperglycemic WT mice vs normoglycemic mice, there was no difference between hyperglycemic EphA2-R-M mice and normoglycemic EphA2-R-M mice. The hypertrophic response that normally occurs in viable myocardium remote to the infarct was noticeably absent in epicardial cardiomyocytes and cardiac dysfunction worsened in hyperglycemic EphA2-R-M hearts post-MI. The characteristic interstitial fibrotic response in the compensating myocardium remote to the infarct also did not occur in hyperglycemic EphA2-R-M mouse hearts to the same extent as that observed in the hyperglycemic WT mouse hearts. Differences in neutrophil and pan-leukocyte infiltration and serum cytokines implicate EphA2-R in modulation of injury and the differences in ephrinA1 and EphA6-R expression in governing this are discussed. Conclusions We conclude that EphA2-mutant mice are more prone to hyperglycemia-induced increased injury, decreased survival, and worsened LV remodeling due to impaired wound healing.en_US
dc.identifier.citationCardiovascular Diabetology; 13: p. 1-16en_US
dc.identifier.doi10.1186/s12933-014-0114-y
dc.identifier.issn1475-2840
dc.identifier.pmidpmc4147179en_US
dc.identifier.urihttp://hdl.handle.net/10342/5799
dc.relation.urihttp://www.ncbi.nlm.nih.gov/pmc/articles/PMC4147179/en_US
dc.subjectDiabetesen_US
dc.subjectIschemiaen_US
dc.subjectMyocardial infarctionen_US
dc.subjectHyperglycemiaen_US
dc.subjectEphrinA1/EphAen_US
dc.titleEphA2-receptor deficiency exacerbates myocardial infarction and reduces survival in hyperglycemic miceen_US
dc.typeArticleen_US
ecu.journal.nameCardiovascular Diabetologyen_US
ecu.journal.pages1-16en_US
ecu.journal.volume13en_US

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