EphrinA1-Fc attenuates myocardial ischemia/reperfusion injury in mice

Autor: Jitka A. I. Virag, Uma M Sharma, David W Wert, Augustin DuSablon, Robert C Chase, Eleftherios Vlahos, K'Shylah S Whitehurst, Justin Parks, Heather K Estes
Rok vydání: 2017
Předmět:
Male
0301 basic medicine
Critical Care and Emergency Medicine
Physiology
Myocardial Infarction
lcsh:Medicine
Apoptosis
030204 cardiovascular system & hematology
Pharmacology
Pathology and Laboratory Medicine
Vascular Medicine
Mice
0302 clinical medicine
Ischemia
Immune Physiology
Medicine and Health Sciences
Myocardial infarction
lcsh:Science
Immune Response
Cardioprotection
Innate Immune System
Multidisciplinary
Cell Death
Ephrin-A1
Heart
Echocardiography
Cell Processes
Cytokines
Anatomy
Signal transduction
medicine.symptom
Research Article
Cardiac function curve
Recombinant Fusion Proteins
Autophagic Cell Death
Immunology
Cardiology
Myocardial Reperfusion Injury
Inflammation
03 medical and health sciences
Signs and Symptoms
Diagnostic Medicine
medicine
Animals
business.industry
lcsh:R
Biology and Life Sciences
Cell Biology
Molecular Development
medicine.disease
Immunoglobulin Fc Fragments
030104 developmental biology
Immune System
Reperfusion
Cardiovascular Anatomy
lcsh:Q
business
Reperfusion injury
Developmental Biology
Zdroj: PLoS ONE
PLoS ONE, Vol 12, Iss 12, p e0189307 (2017)
ISSN: 1932-6203
DOI: 10.1371/journal.pone.0189307
Popis: EphrinA1, a membrane-bound receptor tyrosine kinase ligand expressed in healthy cardiomyocytes, 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 ischemia 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 myocardium. 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 homogenates from mice that underwent 30min ischemia and 24hr of reperfusion (I/R) indicates that ephrinA1-Fc administration alters several regulators of signaling pathways that attenuate apoptosis, promote autophagy, and shift from FA metabolism in favor of increased glycolysis 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.
Databáze: OpenAIRE
Externí odkaz: