Cardiovascular Research Advance Access first published online on September 22, 2007
This version [Accepted Manuscript] published online on October 3, 2007
Cardiovascular Research, doi:10.1093/cvr/cvm026
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HUMAN THROMBOPOIETIN REDUCES MYOCARDIAL INFARCT SIZE, APOPTOSIS AND STUNNING FOLLOWING ISCHEMIA/REPERFUSION IN RATS
1 Division of Cardiothoracic Surgery, 8701 Watertown Plank Rd, Medical College of Wisconsin, Milwaukee, WI 53226
2 Department of Pharmacology and Toxicology, 8701 Watertown Plank Rd, Medical College of Wisconsin, Milwaukee, WI 53226
3 Department of Biochemistry, 8701 Watertown Plank Rd, Medical College of Wisconsin, Milwaukee, WI 53226
5 Department of Biophysics, 8701 Watertown Plank Rd, Medical College of Wisconsin, Milwaukee, WI 53226
6 Department of Medicine, 8701 Watertown Plank Rd, Medical College of Wisconsin, Milwaukee, WI 53226
7 Department of Pathology, 8701 Watertown Plank Rd, Medical College of Wisconsin, Milwaukee, WI 53226
8 Department of Biomedical Resource Center, 8701 Watertown Plank Rd, Medical College of Wisconsin, Milwaukee, WI 53226
9 Department of General Surgery, 8701 Watertown Plank Rd, Medical College of Wisconsin, Milwaukee, WI 53226
4 Children's Hospital Research Institute, 9200 W. Wisconsin Ave., Milwaukee, WI 53226
10 Children's Hospital of Wisconsin, Section of Cardiothoracic Surgery 9200 W. Wisconsin Ave., Milwaukee, WI 53226
Address for correspondence: John E. Baker, Ph.D. Division of Cardiothoracic Surgery, Medical College of Wisconsin 8701 Watertown Plank Road, Milwaukee, WI 53226, U.S.A. Tel: (414) 456-8706, Fax: (414) 453-9700 E-mail: jbaker{at}mcw.edu
Objective: 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: We assessed the potential protective role of Tpo in vitro and in vivo in two rat models of myocardial ischemia/reperfusion.
Results: 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 ischemia reduced myocardial necrosis, apoptosis, and decline in ventricular function following ischemia/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 I.V. in vivo. Tpo also reduced infarct size when given after the onset of ischemia or at reperfusion. Tpo activated JAK-2 and p44 MAPK during reperfusion but not prior to ischemia. 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 ischemia/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 I.V.) did not result in the elevation of platelet count or hematocrit 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 ischemia and reperfusion.
Time for primary review: 13 days
This is a new version as two of the figures were in the wrong order in the previous version.
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Cardiovasc Res 2008 77: 2-3.
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