Abstract 2889: Pyruvate-enriched Cardioplegia Evokes Novel Erythropoietin Expression and Signaling in Porcine Myocardium
Background: Administration of pyruvate-fortified cardioplegia to patients undergoing cardio-pulmonary bypass (CPB) enhanced post-surgical recovery of cardiac function, minimized inotropic support requirements, permitting earlier hospital discharge. Pyruvate reportedly suppresses degradation of the α subunit of hypoxia-inducible factor-1 (HIF-1), an activator of the gene encoding the cardioprotective cytokine erythropoietin (EPO). Exogenous EPO minimizes myocardial ischemia-reperfusion injury, but induction of myocardial EPO expression and signaling has never been reported.
Hypothesis: Pyruvate-enriched cardioplegia evokes novel EPO expression and mobilizes EPO signaling mechanisms in myocardium.
Methods: Hearts of domestic 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 at 4 h recovery for immunoblot measurements of HIF-1α, EPO, EPO receptor (EPO-R), the EPO signaling kinases Akt and Erk, and endothelial nitric oxide synthase (eNOS), a downstream effector of EPO signaling.
Results: Pyruvate-fortified cardioplegia induced myocardial EPO mRNA expression, and increased HIF-1α, EPO and EPO-R protein contents by 60, 58 and 123%, respectively (P<0.05) vs. control cardioplegia. Pyruvate cardioplegia also enhanced Akt and Erk phosphorylation, NOS activity and eNOS content by 38, 76, 45 and 81%, vs. respective values in control cardioplegia-treated myocardium (P<0.05).
Conclusions: By stabilizing HIF-1α, pyruvate-enriched cardioplegia induced novel myocardial EPO expression and activated key elements of EPO’s cardioprotective signaling cascades. These results are the first to demonstrate that cardioplegia can be modified to activate endogenous cardioprotective EPO signaling.