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


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.


CONCLUSIONS
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.
Baker
John E
JE
Division of Cardiothoracic Surgery, Medical College of Wisconsin, 8701 Watertown Plank Road, Milwaukee, WI 53226, USA. jbaker@mcw.edu
Su
Jidong
J
Hsu
Anna
A
Shi
Yang
Y
Zhao
Ming
M
Strande
Jennifer L
JL
Fu
Xiangping
X
Xu
Hao
H
Eis
Annie
A
Komorowski
Richard
R
Jensen
Eric S
ES
Tweddell
James S
JS
Rafiee
Parvaneh
P
Gross
Garrett J
GJ
D000818:Animals; D017209:Apoptosis / Q000187:drug effects*; D048049:Extracellular Signal-Regulated MAP Kinases / Q000502:physiology; D006801:Humans; D066298:In Vitro Techniques; D053614:Janus Kinase 2 / Q000502:physiology; D054086:KATP Channels / Q000502:physiology; D008297:Male; D009203:Myocardial Infarction / Q000188:drug therapy* / Q000473:pathology; D015428:Myocardial Reperfusion Injury / Q000188:drug therapy*; D017682:Myocardial Stunning / Q000188:drug therapy*; D051381:Rats; D017207:Rats, Sprague-Dawley; D050796:STAT3 Transcription Factor / Q000502:physiology; D013926:Thrombopoietin / Q000494:pharmacology / Q000627:therapeutic use*; D013997:Time Factors
D054086:KATP Channels; D050796:STAT3 Transcription Factor; C494088:Stat3 protein, rat; D013926:Thrombopoietin; C507927:Jak2 protein, rat; D053614:Janus Kinase 2; D048049:Extracellular Signal-Regulated MAP Kinases