Pyruvate-fortified cardioplegia evokes myocardial erythropoietin signaling in swine undergoing cardiopulmonary bypass

Ryou MG, Flaherty DC, Hoxha B, Sun J, Gurji H, Rodriguez S, Bell G, Olivencia-Yurvati AH, Mallet RT. Pyruvate-fortified cardioplegia evokes myocardial erythropoietin signaling in swine undergoing cardiopulmonary bypass. Am J Physiol Heart Circ Physiol 297: H1914-H1922, 2009. First published September 18, 2009; doi:10.1152/ajpheart.01213.2008.-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 +/- 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-1 alpha, 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-1 alpha, 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-ERKeNOS mechanism. By stabilizing HIF-1 alpha, pyruvate-fortified cardioplegia may evoke sustained activation of EPO's cardioprotective signaling cascade in myocardium.