EphA2-receptor deficiency exacerbates myocardial infarction and reduces survival in hyperglycemic miceReportar como inadecuado




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Cardiovascular Diabetology

, 13:114

First Online: 13 August 2014Received: 19 March 2014Accepted: 12 July 2014

Abstract

BackgroundWe 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.

MethodsStreptozotocin 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 p < 0.05.

ResultsBoth 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.

ConclusionsWe conclude that EphA2-mutant mice are more prone to hyperglycemia-induced increased injury, decreased survival, and worsened LV remodeling due to impaired wound healing.

KeywordsDiabetes Ischemia Myocardial infarction Hyperglycemia EphrinA1-EphA Electronic supplementary materialThe online version of this article doi:10.1186-s12933-014-0114-y contains supplementary material, which is available to authorized users.

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Autor: Augustin DuSablon - Susan Kent - Anita Coburn - Jitka Virag

Fuente: https://link.springer.com/article/10.1186/s12933-014-0114-y







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