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Cardiovascular Research Advance Access originally published online on September 22, 2007
Cardiovascular Research 2008 77(1):44-53; doi:10.1093/cvr/cvm026
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Published on behalf of the European Society of Cardiology. All rights reserved. © The Author 2007. For permissions please email: journals.permissions@oxfordjournals.org

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

John E. Baker1,2,3,4,*, Jidong Su1,4, Anna Hsu2, Yang Shi1, Ming Zhao5, Jennifer L. Strande6, Xiangping Fu1,4, Hao Xu1, Annie Eis6, Richard Komorowski7, Eric S. Jensen8, James S. Tweddell1,4,9, Parvaneh Rafiee10 and Garrett J. Gross2

1 Division of Cardiothoracic Surgery, Medical College of Wisconsin, 8701 Watertown Plank Road, Milwaukee, WI 53226, USA
2 Department of Pharmacology and Toxicology, Medical College of Wisconsin, 8701 Watertown Plank Road, Milwaukee, WI 53226, USA
3 Department of Biochemistry, Medical College of Wisconsin, 8701 Watertown Plank Road, Milwaukee, WI 53226, USA
4 Children’s Hospital Research Institute, 9200 W. Wisconsin Avenue, Milwaukee, WI 53226, USA
5 Department of Biophysics, Medical College of Wisconsin, 8701 Watertown Plank Road, Milwaukee, WI 53226, USA
6 Department of Medicine, Medical College of Wisconsin, 8701 Watertown Plank Road, Milwaukee, WI 53226, USA
7 Department of Pathology, 8701 Watertown Plank Road, Medical College of Wisconsin, Milwaukee, WI 53226, USA
8 Biomedical Resource Center, Medical College of Wisconsin, 8701 Watertown Plank Road, Milwaukee, WI 53226, USA
9 Section of Cardiothoracic Surgery, Children’s Hospital of Wisconsin, 9200 W. Wisconsin Avenue, Milwaukee, WI 53226, USA
10 Department of General Surgery, Medical College of Wisconsin, 8701 Watertown Plank Road, Milwaukee, WI 53226, USA

* Corresponding author. Tel: +1 414 456 8706; fax: +1 414 453 9700. E-mail address: jbaker{at}mcw.edu

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.

KEYWORDS Ischaemia; thrombopoietin; protein kinases; infarction; K-ATP channel

Time for primary review 13 days


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