Pyruvate-fortified cardioplegia evokes myocardial erythropoietin signaling in swine undergoing cardiopulmonary bypass.
Pyruvate-fortified cardioplegia protects myocardium and hastens postsurgical recovery of patients undergoing cardiopulmonary bypass (CPB). Pyruvate reportedly suppresses degradation of the alpha-subunit of hypoxia-inducible factor-1 (HIF-1), an activator of the gene encoding the cardioprotective cytokine erythropoietin (EPO). This study tested the hypothesis that pyruvate-enriched cardioplegia evoked EPO expression and mobilized EPO signaling mechanisms in myocardium. Hearts of pigs maintained on CPB were arrested for 60 min with 4:1 blood-crystalloid cardioplegia. The crystalloid component contained 188 mM glucose + or - 24 mM pyruvate. After 30-min cardiac reperfusion with cardioplegia-free blood, the pigs were weaned from CPB. Left ventricular myocardium was sampled 4 h after CPB for immunoblot assessment of HIF-1alpha, EPO and its receptor, the signaling kinases Akt and ERK, and endothelial nitric oxide synthase (eNOS), an effector of EPO signaling. Pyruvate-fortified cardioplegia stabilized arterial pressure post-CPB, induced myocardial EPO mRNA expression, and increased HIF-1alpha, EPO, and EPO-R protein contents by 60, 58, and 123%, respectively, vs. control cardioplegia (P < 0.05). Pyruvate cardioplegia also increased ERK phosphorylation by 61 and 118%, respectively, vs. control cardioplegia-treated and non-CPB sham myocardium (P < 0.01), but did not alter Akt phosphorylation. Nitric oxide synthase (NOS) activity and eNOS content fell 32% following control CPB vs. sham, but pyruvate cardioplegia prevented these declines, yielding 49 and 80% greater NOS activity and eNOS content vs. respective control values (P < 0.01). Pyruvate-fortified cardioplegia induced myocardial EPO expression and mobilized the EPO-ERK-eNOS mechanism. By stabilizing HIF-1alpha, pyruvate-fortified cardioplegia may evoke sustained activation of EPO's cardioprotective signaling cascade in myocardium.
Ryou
Myoung-Gwi
MG
Department of Integrative Physiology, University of North Texas, Health Science Center, 3500 Camp Bowie Blvd., Fort Worth, TX 76107-2699, USA.
Flaherty
Devin C
DC
Hoxha
Besim
B
Sun
Jie
J
Gurji
Hunaid
H
Rodriguez
Steven
S
Bell
Glenn
G
Olivencia-Yurvati
Albert H
AH
Mallet
Robert T
RT
D000818:Animals; D001794:Blood Pressure / Q000187:drug effects; D002314:Cardioplegic Solutions / Q000378:metabolism / Q000494:pharmacology*; D002315:Cardiopulmonary Bypass / Q000009:adverse effects; D004489:Edema, Cardiac / Q000209:etiology / Q000378:metabolism / Q000517:prevention & control; D004734:Energy Metabolism; D004921:Erythropoietin / Q000235:genetics / Q000378:metabolism*; D048049:Extracellular Signal-Regulated MAP Kinases / Q000378:metabolism; D005260:Female; D005978:Glutathione / Q000378:metabolism; D006324:Heart Arrest, Induced / Q000009:adverse effects / Q000379:methods*; D006331:Heart Diseases / Q000209:etiology / Q000378:metabolism / Q000503:physiopathology / Q000517:prevention & control*; D006339:Heart Rate / Q000187:drug effects; D006352:Heart Ventricles / Q000187:drug effects / Q000378:metabolism; D051795:Hypoxia-Inducible Factor 1, alpha Subunit / Q000235:genetics / Q000378:metabolism; D008297:Male; D023421:Models, Animal; D009206:Myocardium / Q000378:metabolism*; D052250:Nitric Oxide Synthase Type III / Q000378:metabolism; D010084:Oxidation-Reduction; D010766:Phosphorylation; D051057:Proto-Oncogene Proteins c-akt / Q000378:metabolism; D019289:Pyruvic Acid / Q000378:metabolism / Q000494:pharmacology*; D012333:RNA, Messenger / Q000378:metabolism; D017467:Receptors, Erythropoietin / Q000378:metabolism; D015398:Signal Transduction / Q000187:drug effects*; D013552:Swine; D013997:Time Factors; D015854:Up-Regulation
D002314:Cardioplegic Solutions; D051795:Hypoxia-Inducible Factor 1, alpha Subunit; D012333:RNA, Messenger; D017467:Receptors, Erythropoietin; D004921:Erythropoietin; D019289:Pyruvic Acid; D052250:Nitric Oxide Synthase Type III; D051057:Proto-Oncogene Proteins c-akt; D048049:Extracellular Signal-Regulated MAP Kinases; D005978:Glutathione