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Human thrombopoietin reduces myocardial infarct size, apoptosis, and stunning following ischaemia/reperfusion in rats. Cardiovasc Res 2008 Jan;77(1):44-53

Date

11/17/2007

Pubmed ID

18006466

Pubmed Central ID

PMC2958050

DOI

10.1093/cvr/cvm026

Scopus ID

2-s2.0-38849176235   30 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 microg/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 K(ATP) channels (5-HD), and sarcolemmal K(ATP) 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 microg/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 K(ATP) channels, suggesting a potential therapeutic role of Tpo in the treatment of injury resulting from myocardial ischaemia and reperfusion.

Author List

Baker JE, Su J, Hsu A, Shi Y, Zhao M, Strande JL, Fu X, Xu H, Eis A, Komorowski R, Jensen ES, Tweddell JS, Rafiee P, Gross GJ

Authors

John E. Baker PhD Professor in the Surgery department at Medical College of Wisconsin
Eric S. Jensen DVM Associate Professor in the Research Office department at Medical College of Wisconsin




MESH terms used to index this publication - Major topics in bold

Animals
Apoptosis
Extracellular Signal-Regulated MAP Kinases
Humans
In Vitro Techniques
Janus Kinase 2
KATP Channels
Male
Myocardial Infarction
Myocardial Reperfusion Injury
Myocardial Stunning
Rats
Rats, Sprague-Dawley
STAT3 Transcription Factor
Thrombopoietin
Time Factors
jenkins-FCD Prod-482 91ad8a360b6da540234915ea01ff80e38bfdb40a