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

Myoung Gwi Ryou, Devin C. Flaherty, Besim Hoxha, Jie Sun, Hunaid Gurji, Steven Rodriguez, Glenn Bell, Albert Yurvati, Robert T. Mallet

Research output: Contribution to journalArticleResearchpeer-review

16 Citations (Scopus)

Abstract

Pyruvate-fortified cardioplegia protects myocardium and hastens postsurgical recovery of patients undergoing cardiopulmonary bypass (CPB). 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). 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-1α, 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-1α, 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 EPOERK-eNOS mechanism. By stabilizing HIF-1α, pyruvate-fortified cardioplegia may evoke sustained activation of EPO's cardioprotective signaling cascade in myocardium.

Original languageEnglish
JournalAmerican Journal of Physiology - Heart and Circulatory Physiology
Volume297
Issue number5
DOIs
StatePublished - 1 Nov 2009

Fingerprint

Induced Heart Arrest
Erythropoietin
Cardiopulmonary Bypass
Pyruvic Acid
Swine
Hypoxia-Inducible Factor 1
Nitric Oxide Synthase Type III
Myocardium
Nitric Oxide Synthase
Phosphorylation
Erythropoietin Receptors
Reperfusion
Arterial Pressure
Phosphotransferases
Cytokines

Keywords

  • Endothelial nitric oxide synthase
  • Hypoxia-inducible factor

Cite this

Ryou, Myoung Gwi ; Flaherty, Devin C. ; Hoxha, Besim ; Sun, Jie ; Gurji, Hunaid ; Rodriguez, Steven ; Bell, Glenn ; Yurvati, Albert ; Mallet, Robert T. / Pyruvate-fortified cardioplegia evokes myocardial erythropoietin signaling in swine undergoing cardiopulmonary bypass. In: American Journal of Physiology - Heart and Circulatory Physiology. 2009 ; Vol. 297, No. 5.
@article{92234aaa339d4777a46df2fca29fed5d,
title = "Pyruvate-fortified cardioplegia evokes myocardial erythropoietin signaling in swine undergoing cardiopulmonary bypass",
abstract = "Pyruvate-fortified cardioplegia protects myocardium and hastens postsurgical recovery of patients undergoing cardiopulmonary bypass (CPB). 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). 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-1α, 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-1α, 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 EPOERK-eNOS mechanism. By stabilizing HIF-1α, pyruvate-fortified cardioplegia may evoke sustained activation of EPO's cardioprotective signaling cascade in myocardium.",
keywords = "Endothelial nitric oxide synthase, Hypoxia-inducible factor",
author = "Ryou, {Myoung Gwi} and Flaherty, {Devin C.} and Besim Hoxha and Jie Sun and Hunaid Gurji and Steven Rodriguez and Glenn Bell and Albert Yurvati and Mallet, {Robert T.}",
year = "2009",
month = "11",
day = "1",
doi = "10.1152/ajpheart.01213.2008",
language = "English",
volume = "297",
journal = "American Journal of Physiology - Heart and Circulatory Physiology",
issn = "0363-6135",
publisher = "American Physiological Society",
number = "5",

}

Pyruvate-fortified cardioplegia evokes myocardial erythropoietin signaling in swine undergoing cardiopulmonary bypass. / Ryou, Myoung Gwi; Flaherty, Devin C.; Hoxha, Besim; Sun, Jie; Gurji, Hunaid; Rodriguez, Steven; Bell, Glenn; Yurvati, Albert; Mallet, Robert T.

In: American Journal of Physiology - Heart and Circulatory Physiology, Vol. 297, No. 5, 01.11.2009.

Research output: Contribution to journalArticleResearchpeer-review

TY - JOUR

T1 - Pyruvate-fortified cardioplegia evokes myocardial erythropoietin signaling in swine undergoing cardiopulmonary bypass

AU - Ryou, Myoung Gwi

AU - Flaherty, Devin C.

AU - Hoxha, Besim

AU - Sun, Jie

AU - Gurji, Hunaid

AU - Rodriguez, Steven

AU - Bell, Glenn

AU - Yurvati, Albert

AU - Mallet, Robert T.

PY - 2009/11/1

Y1 - 2009/11/1

N2 - Pyruvate-fortified cardioplegia protects myocardium and hastens postsurgical recovery of patients undergoing cardiopulmonary bypass (CPB). 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). 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-1α, 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-1α, 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 EPOERK-eNOS mechanism. By stabilizing HIF-1α, pyruvate-fortified cardioplegia may evoke sustained activation of EPO's cardioprotective signaling cascade in myocardium.

AB - Pyruvate-fortified cardioplegia protects myocardium and hastens postsurgical recovery of patients undergoing cardiopulmonary bypass (CPB). 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). 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-1α, 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-1α, 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 EPOERK-eNOS mechanism. By stabilizing HIF-1α, pyruvate-fortified cardioplegia may evoke sustained activation of EPO's cardioprotective signaling cascade in myocardium.

KW - Endothelial nitric oxide synthase

KW - Hypoxia-inducible factor

UR - http://www.scopus.com/inward/record.url?scp=70350464508&partnerID=8YFLogxK

U2 - 10.1152/ajpheart.01213.2008

DO - 10.1152/ajpheart.01213.2008

M3 - Article

VL - 297

JO - American Journal of Physiology - Heart and Circulatory Physiology

JF - American Journal of Physiology - Heart and Circulatory Physiology

SN - 0363-6135

IS - 5

ER -