EphA2-receptor deficiency exacerbates myocardial infarction and reduces survival in hyperglycemic mice
DuSablon, Augustin; Kent, Susan; Coburn, Anita; Virag, Jitka A. I.
Background 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 p < 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.
DuSablon, Augustin, & Kent, Susan, & Coburn, Anita, & Virag, Jitka A. I.. (August 2014). EphA2-receptor deficiency exacerbates myocardial infarction and reduces survival in hyperglycemic mice. Cardiovascular Diabetology, 13(), 1- 16. Retrieved from http://hdl.handle.net/10342/5799
DuSablon, Augustin, and Kent, Susan, and Coburn, Anita, and Virag, Jitka A. I.. "EphA2-receptor deficiency exacerbates myocardial infarction and reduces survival in hyperglycemic mice". Cardiovascular Diabetology. 13:. (1-16), August 2014. April 18, 2019. http://hdl.handle.net/10342/5799.
DuSablon, Augustin and Kent, Susan and Coburn, Anita and Virag, Jitka A. I., "EphA2-receptor deficiency exacerbates myocardial infarction and reduces survival in hyperglycemic mice," Cardiovascular Diabetology 13, no. (August 2014), http://hdl.handle.net/10342/5799 (accessed April 18, 2019).
DuSablon, Augustin, Kent, Susan, Coburn, Anita, Virag, Jitka A. I.. EphA2-receptor deficiency exacerbates myocardial infarction and reduces survival in hyperglycemic mice. Cardiovascular Diabetology. August 2014; 13(): 1-16. http://hdl.handle.net/10342/5799. Accessed April 18, 2019.