Human thrombopoietin reduces myocardial infarct size, apoptosis, and stunning following ischaemia/reperfusion in rats

John E. Baker*, Jidong Su, Anna Hsu, Yang Shi, Ming Zhao, Jennifer L. Strande, Xiangping Fu, Hao Xu, Annie Eis, Richard Komorowski, Eric S. Jensen, James S. Tweddell, Parvaneh Rafiee, Garrett J. Gross

*Corresponding author for this work

Research output: Contribution to journalArticlepeer-review

30 Scopus citations

Abstract

Aims: Thrombopoietin (Tpo) is known for its ability to stimulate platelet production. However, it is currently unknown whether Tpo plays a physiological function in the heart. Methods and results: We assessed the potential protective role of Tpo in vitro and in vivo in two rat models of myocardial ischaemia/reperfusion. Tpo receptor (c-mpl) message was detected in the heart using RT-PCR, and the Tpo receptor protein was detected using western blotting and immunohistochemistry. Tpo treatment immediately before ischaemia reduced myocardial necrosis, apoptosis, and decline in ventricular function following ischaemia/reperfusion in the rat in a concentration- and dose-dependent manner with an optimal concentration of 1.0 ng/mL in vitro and an optimal dose of 0.05 μg/kg iv in vivo. Tpo also reduced infarct size when given after the onset of ischaemia or at reperfusion. Tpo activated JAK-2 (Janus kinase-2) and p44 MAPK (mitogen-activated protein kinase) during reperfusion but not prior to ischaemia. Inhibition of JAK-2 (AG-490), p42/44 MAPK (PD98059), mitochondrial KATP channels (5-HD), and sarcolemmal KATP channels (HMR 1098) abolished Tpo-induced resistance to injury from myocardial ischaemia/reperfusion. AG-490, PD98059, 5-HD, and HMR1098 alone had no effect on cardioprotection. Treatment with a single dose of Tpo (0.05 or 1.0 μg/kg iv) did not result in the elevation of platelet count or haematocrit over a 16-day period. Conclusion: A single treatment of Tpo confers cardioprotection through JAK-2, p42/44 MAPK, and KATP channels, suggesting a potential therapeutic role of Tpo in the treatment of injury resulting from myocardial ischaemia and reperfusion.

Original languageEnglish (US)
Pages (from-to)44-53
Number of pages10
JournalCardiovascular research
Volume77
Issue number1
DOIs
StatePublished - Jan 2008

Keywords

  • Infarction
  • Ischaemia
  • K-ATP channel
  • Protein kinases
  • Thrombopoietin

ASJC Scopus subject areas

  • Physiology
  • Cardiology and Cardiovascular Medicine
  • Physiology (medical)

Fingerprint Dive into the research topics of 'Human thrombopoietin reduces myocardial infarct size, apoptosis, and stunning following ischaemia/reperfusion in rats'. Together they form a unique fingerprint.

Cite this