Chronic Treatment With an Erythropoietin Receptor Ligand Prevents Chronic Kidney Disease-Induced Enlargement of Myocardial Infarct Size.
2016
Chronic kidney disease (CKD) is known to increase myocardial infarct size after ischemia/reperfusion. However, a strategy to prevent the CKD-induced myocardial susceptibility to ischemia/
reperfusion injuryhas not been developed. Here, we examined whether epoetin β pegol, a
continuous erythropoietin receptor activator(CERA), normalizes myocardial susceptibility to ischemia/
reperfusion injuryby its effects on protective signaling and metabolomes in CKD. CKD was induced by 5/6 nephrectomy in rats (subtotal nephrectomy, SNx), whereas sham-operated rats served controls (Sham). Infarct size as percentage of area at risk after 20-minutes
coronary occlusion/2-hour reperfusion was larger in SNx than in Sham: 60.0±4.0% versus 43.9±2.2%. Administration of CERA (0.6 μg/kg SC every 7 days) for 4 weeks reduced infarct size in SNx (infarct size as percentage of area at risk=36.9±3.9%), although a protective effect was not detected for the acute injection of CERA. Immunoblot analyses revealed that myocardial phospho-Akt-Ser473 levels under baseline conditions and on reperfusion were lower in SNx than in Sham, and CERA restored the Akt phosphorylation on reperfusion. Metabolomic analyses showed that glucose 6-phosphate and
glucose 1-phosphatewere reduced and malate:aspartate ratio was 1.6-fold higher in SNx than in Sham, suggesting disturbed flux of
malate–aspartate shuttleby CKD. The CERA improved the malate:aspartate ratio in SNx to the control level. In H9c2 cells, mitochondrial Akt phosphorylation by insulin-like growth factor-1 was attenuated by
malate–aspartate shuttleinhibition. In conclusion, the results suggest that a CERA prevents CKD-induced susceptibility of the myocardium to ischemia/
reperfusion injuryby restoration of Akt-mediated signaling possibly via normalized
malate–aspartate shuttleflux.
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