title: Chronic Treatment With an Erythropoietin Receptor Ligand Prevents Chronic Kidney Disease-Induced Enlargement of Myocardial Infarct Size.
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 injury by restoration of Akt-mediated signaling possibly via normalized malate-aspartate shuttle flux.
authors.affiliation: Departments of Cardiovascular, Renal, and Metabolic Medicine (K.N., T.Y., M.T., T.M., A.K., T.T., M.O., S.M., K.O., S.I., T.M.) and Pharmacology (A.K.), Sapporo Medical University School of Medicine, Japan.
authors.forename: Keitaro
authors.initials: K
authors.lastname: Nishizawa
authors.affiliation: Departments of Cardiovascular, Renal, and Metabolic Medicine (K.N., T.Y., M.T., T.M., A.K., T.T., M.O., S.M., K.O., S.I., T.M.) and Pharmacology (A.K.), Sapporo Medical University School of Medicine, Japan.
authors.forename: Toshiyuki
authors.initials: T
authors.lastname: Yano
authors.affiliation: Departments of Cardiovascular, Renal, and Metabolic Medicine (K.N., T.Y., M.T., T.M., A.K., T.T., M.O., S.M., K.O., S.I., T.M.) and Pharmacology (A.K.), Sapporo Medical University School of Medicine, Japan.
authors.forename: Masaya
authors.initials: M
authors.lastname: Tanno
authors.affiliation: Departments of Cardiovascular, Renal, and Metabolic Medicine (K.N., T.Y., M.T., T.M., A.K., T.T., M.O., S.M., K.O., S.I., T.M.) and Pharmacology (A.K.), Sapporo Medical University School of Medicine, Japan.
authors.forename: Takayuki
authors.initials: T
authors.lastname: Miki
authors.affiliation: Departments of Cardiovascular, Renal, and Metabolic Medicine (K.N., T.Y., M.T., T.M., A.K., T.T., M.O., S.M., K.O., S.I., T.M.) and Pharmacology (A.K.), Sapporo Medical University School of Medicine, Japan.
authors.forename: Atsushi
authors.initials: A
authors.lastname: Kuno
authors.affiliation: Departments of Cardiovascular, Renal, and Metabolic Medicine (K.N., T.Y., M.T., T.M., A.K., T.T., M.O., S.M., K.O., S.I., T.M.) and Pharmacology (A.K.), Sapporo Medical University School of Medicine, Japan.
authors.forename: Toshiyuki
authors.initials: T
authors.lastname: Tobisawa
authors.affiliation: Departments of Cardiovascular, Renal, and Metabolic Medicine (K.N., T.Y., M.T., T.M., A.K., T.T., M.O., S.M., K.O., S.I., T.M.) and Pharmacology (A.K.), Sapporo Medical University School of Medicine, Japan.
authors.forename: Makoto
authors.initials: M
authors.lastname: Ogasawara
authors.affiliation: Departments of Cardiovascular, Renal, and Metabolic Medicine (K.N., T.Y., M.T., T.M., A.K., T.T., M.O., S.M., K.O., S.I., T.M.) and Pharmacology (A.K.), Sapporo Medical University School of Medicine, Japan.
authors.forename: Shingo
authors.initials: S
authors.lastname: Muratsubaki
authors.affiliation: Departments of Cardiovascular, Renal, and Metabolic Medicine (K.N., T.Y., M.T., T.M., A.K., T.T., M.O., S.M., K.O., S.I., T.M.) and Pharmacology (A.K.), Sapporo Medical University School of Medicine, Japan.
authors.forename: Kouhei
authors.initials: K
authors.lastname: Ohno
authors.affiliation: Departments of Cardiovascular, Renal, and Metabolic Medicine (K.N., T.Y., M.T., T.M., A.K., T.T., M.O., S.M., K.O., S.I., T.M.) and Pharmacology (A.K.), Sapporo Medical University School of Medicine, Japan.
authors.forename: Satoko
authors.initials: S
authors.lastname: Ishikawa
authors.affiliation: Departments of Cardiovascular, Renal, and Metabolic Medicine (K.N., T.Y., M.T., T.M., A.K., T.T., M.O., S.M., K.O., S.I., T.M.) and Pharmacology (A.K.), Sapporo Medical University School of Medicine, Japan. miura@sapmed.ac.jp.
authors.forename: Tetsuji
authors.initials: T
authors.lastname: Miura
mesh_terms: D000704:Analysis of Variance; D000818:Animals; D004195:Disease Models, Animal; D004334:Drug Administration Schedule; D004921:Erythropoietin / Q000494:pharmacology*; D007279:Injections, Subcutaneous; D008297:Male; D055442:Metabolome; D009203:Myocardial Infarction / Q000209:etiology / Q000517:prevention & control*; D015428:Myocardial Reperfusion Injury / Q000517:prevention & control*; D009392:Nephrectomy; D010766:Phosphorylation; D011092:Polyethylene Glycols / Q000494:pharmacology*; D051057:Proto-Oncogene Proteins c-akt / Q000187:drug effects* / Q000378:metabolism; D011897:Random Allocation; D051381:Rats; D012016:Reference Values; D051436:Renal Insufficiency, Chronic / Q000150:complications / Q000503:physiopathology*; D012680:Sensitivity and Specificity
chemical_list: C508420:continuous erythropoietin receptor activator; D004921:Erythropoietin; D011092:Polyethylene Glycols; D051057:Proto-Oncogene Proteins c-akt
keywords: chronic kidney disease; erythropoietin; metabolome; myocardial infarction; signal transduction