Chronic Treatment With an Erythropoietin Receptor Ligand Prevents Chronic Kidney Disease–Induced Enlargement of Myocardial Infarct Size

Abstract

We recently found that insufficient activation of Akt-mediated signaling underlies aggravation of reperfusion injury, leading to enlarged infarct size. 6 In addition to modified signal transduction, alteration in metabolism is possibly involved in CKD-induced increase in myocardial sensitivity to ischemia/ reperfusion (I/R) injury. Insulin resistance is a metabolic hallmark of uremia, 7,8 and Tamaki et al 9 showed that CKD induces substantial changes in metabolites and the number of mitochondria in skeletal muscle. However, to our knowledge, the effect of CKD on cardiac metabolomes has not been reported, and its relationship to modification of the cytoprotective signal pathway also remains unclear.Erythropoietin is produced in the adult kidney and plays a major role in promotion of erythropoiesis. However, erythropoietin protein is also expressed in nonrenal tissues, including the liver and central nervous system. 10 Erythropoietin receptors are also expressed not only in hematopoietic cells but also in other types of cells, such as endothelial cells, neurons, and cardiomyocytes. [11][12][13] A series of studies using a mutant mouse that expresses the erythropoietin receptor exclusively in hematopoietic cells (EpoR −/− rescued) showed that deletion of the erythropoietin receptor aggravates I/R injury and Abstract-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 injury has not been developed. Here, we examined whether epoetin β pegol, a continuous erythropoietin receptor activator (CERA), normalizes myocardial susceptibility to ischemia/reperfusion injury by 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-phosphate were reduced and malate:aspartate ratio was 1.6-fold higher in SNx than in Sham, suggesting disturbed flux of malate-aspartate shuttle by 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 shuttle inhibition. In conclusion, the results suggest that a CERA prevents CKD-induced susceptibility of the myocardium to ischemia/reperfusion in...

Insufficient activation of Akt upon reperfusion because of its novel modification by reduced PP2A-B55α contributes to enlargement of infarct size by chronic kidney disease

“…Since EPO has been shown to be a cardioprotective molecule, it might be speculated that reduction in circulating EPO level contributes to infarct size enlargement by CKD. However, this possibility was not supported by the results of a study [26] conducted in parallel with the present study. In the second protocol of that study, we determined serum EPO levels in the same rat CKD model and sham-operated rats as those in the present study.…”

“…In fact, mitochondrial dysfunction [36] and down-regulated expression of the adiponectin receptor in the myocardium [35] were reported to be associated with increased myocardial injury by CKD. In our study conducted in parallel with this study [26], disturbed malate-aspartate shuttle in the myocardium in CKD was indicated by results of metabolome analysis. Relationships between mitochondrial dysfunction, impaired response of cytoprotective signaling, and duration and severity of renal dysfunction remain to be investigated.…”

“…In the second protocol of that study, we determined serum EPO levels in the same rat CKD model and sham-operated rats as those in the present study. There was no significant difference between the serum EPO levels in the SNx and Sham groups (0.9 ± 0.3 vs. 0.5 ± 0.2 mIU/ml), while hemoglobin level was lower in the SNx group (13.8 ± 0.5 vs. 17.1 ± 0.4 g/dl, p \ 0.05), indicating insufficient EPO production in response to anemia, a phenotype of renal anemia, in the SNx group [26]. Post hoc calculation of a correlation coefficient between infarct size as a percent of area at risk and serum EPO level in the SNx group (r = 0.437, p = 0.327) argued against role of circulating EPO in infarct size enlargement by CKD.…”

“…The cells were cultured in DMEM (4.5 g/l glucose) supplemented with 10% fetal bovine serum and antibiotics as reported previously [26,27].…”

The effect of milrinone on mortality in adult patients: A systematic review of randomized clinical trials with meta-analysis and trial sequential analysis

“…[11][12][13] Although CABG surgery has been reported with respect to low costs, superior outcomes, and particularly to short-term mortality, [14][15][16][17] multiple complications such as myocardial infarction (MI), myocardial ischemia, arrhythmias, stroke, and acute renal failure (ARF) are impossible to ignore and still perplex researchers and clinical doctors. 8,[18][19][20][21] To minimize the occurrence of postoperative complications, pre-and/or postoperative medicinal applications, such as phosphodiesterase (PDE) III inhibitors, have been primary strategies until now. [22][23][24] By reducing the inactivation of cyclic adenosine phosphate (cAMP) in cardiomyocytes, PDE III inhibitors enhance myocardial contractility and produce positive inotropic effects; 25,26 a higher concentration of cAMP results in contractility, increasing myocardial tissue and the vasodilatory effect on vascular smooth muscle.…”