EphrinA1-Fc attenuates myocardial ischemia/ reperfusion injury in mice
DuSablon, Augustin; Parks, Justin; Whitehurst, K’Shylah; Estes, Heather; Chase, Robert; Vlahos, Eleftherios; Sharma, Uma; Wert, David; Virag, Jitka
EphrinA1, a membrane-bound receptor tyrosine kinase ligand expressed in healthy car- diomyocytes, is lost in injured cells following myocardial infarction. Previously, we have reported that a single intramyocardial injection of chimeric ephrinA1-Fc at the time of ische- mia reduced injury in the nonreperfused myocardium by 50% at 4 days post-MI by reducing apoptosis and inflammatory cell infiltration. In a clinically relevant model of acute ischemia (30min)/reperfusion (24hr or 4 days) injury, we now demonstrate that ephrinA1-Fc reduces infarct size by 46% and completely preserves cardiac function (ejection fraction, fractional shortening, and chamber dimensions) in the short-term (24hrs post-MI) as well as long-term (4 days). At 24 hours post-MI, diminished serum inflammatory cell chemoattractants in ephrinA1-Fc-treated mice reduces recruitment of neutrophils and leukocytes into the myo- cardium. Differences in relative expression levels of EphA-Rs are described in the context of their putative role in mediating cardioprotection. Validation by Western blotting of selected targets from mass spectrometry analyses of pooled samples of left ventricular tissue ho- mogenates from mice that underwent 30min ischemia and 24hr of reperfusion (I/R) indicates that ephrinA1-Fc administration alters several regulators of signaling pathways that attenu- ate apoptosis, promote autophagy, and shift from FA metabolism in favor of increased gly- colysis to optimize anaerobic ATP production. Taken together, reduced injury is due a combination of adaptive metabolic reprogramming, improved cell survival, and decreased inflammatory cell recruitment, suggesting that ephrinA1-Fc enhances the capacity of the heart to withstand an ischemic insult.
DuSablon, Augustin, & Parks, Justin, & Whitehurst, K’Shylah, & Estes, Heather, & Chase, Robert, & Vlahos, Eleftherios, & Sharma, Uma, & Wert, David, & Virag, Jitka. (December 2017). EphrinA1-Fc attenuates myocardial ischemia/ reperfusion injury in mice. PLoS One, (12:12), p.. Retrieved from http://hdl.handle.net/10342/8179
DuSablon, Augustin, and Parks, Justin, and Whitehurst, K’Shylah, and Estes, Heather, and Chase, Robert, and Vlahos, Eleftherios, and Sharma, Uma, and Wert, David, and Virag, Jitka. "EphrinA1-Fc attenuates myocardial ischemia/ reperfusion injury in mice". PLoS One. 12:12. (.), December 2017. October 25, 2020. http://hdl.handle.net/10342/8179.
DuSablon, Augustin and Parks, Justin and Whitehurst, K’Shylah and Estes, Heather and Chase, Robert and Vlahos, Eleftherios and Sharma, Uma and Wert, David and Virag, Jitka, "EphrinA1-Fc attenuates myocardial ischemia/ reperfusion injury in mice," PLoS One 12, no. 12 (December 2017), http://hdl.handle.net/10342/8179 (accessed October 25, 2020).
DuSablon, Augustin, Parks, Justin, Whitehurst, K’Shylah, Estes, Heather, Chase, Robert, Vlahos, Eleftherios, Sharma, Uma, Wert, David, Virag, Jitka. EphrinA1-Fc attenuates myocardial ischemia/ reperfusion injury in mice. PLoS One. December 2017; 12(12) . http://hdl.handle.net/10342/8179. Accessed October 25, 2020.