Metallothionein mediates cardioprotection of isoliquiritigenin against ischemia-reperfusion through JAK2/STAT3 activation.
OBJECTIVE
To examine whether isoliquiritigenin (ISL) can attenuate myocardial ischemiareperfusion (MI/R) injury in rats by inducing metallothionein (MT) through activation of janus kinase 2 (JAK 2)/signal transducers and activators of transcription 3 (STAT 3) pathway.


METHODS
The experimental model of MI/R in rats was generated by 30 min of ischemia and reperfusion for 2 h. The mRNA expression of MT, COX-2, and iNOS were measured by RT-PCR. The protein expressions of MT, JAK/STAT, extracellular signal-regulated kinase (ERK), and Akt were determined by Western blotting in the absence or presence of a JAK kinase inhibitor, tyrphostin AG490 (1.0 mg/kg, iv, 1 h before ischemia).


RESULTS
Pretreatment with ISL markedly decreased the severity of reperfusion-induced arrhythmias and myocardial infarct size. In the ISL 20 mg/kg group, the activities of lactate dehydrogenase (LDH) and creatinine phosphokinase (CPK) were reduced by 38.4% and 51.3% when compared with the vehicle group. Increased JAK 2/STAT 3 phosphorylation was accompanied by increased synthesis of MT but not of COX-2 or iNOS in ISL-treated groups. AG490 can significantly weaken ISL-induced cardioprotection and prevent the increase of MT expression and JAK 2/STAT 3 phosphorylation.


CONCLUSIONS
ISL protected MI/R injury through activation of JAK 2/STAT 3 signal transduction pathway, which might be involved in mediating the upregulation of MT expression.
An
Wei
W
Department of Pharmacology, School of Medicine, Wuhan University, Wuhan 430071, China.
Yang
Jing
J
Ao
Ying
Y
D000818:Animals; D047188:Chalcones / Q000494:pharmacology*; D003402:Creatine Kinase / Q000378:metabolism; D053614:Janus Kinase 2 / Q000378:metabolism*; D007770:L-Lactate Dehydrogenase / Q000378:metabolism; D008297:Male; D008668:Metallothionein / Q000235:genetics / Q000502:physiology*; D015428:Myocardial Reperfusion Injury / Q000378:metabolism* / Q000473:pathology; D010766:Phosphorylation / Q000187:drug effects; D020011:Protective Agents / Q000494:pharmacology; D011505:Protein-Tyrosine Kinases / Q000037:antagonists & inhibitors; D012333:RNA, Messenger / Q000235:genetics; D051381:Rats; D017207:Rats, Sprague-Dawley; D050796:STAT3 Transcription Factor / Q000378:metabolism*; D015398:Signal Transduction; D020032:Tyrphostins / Q000494:pharmacology
D047188:Chalcones; D020011:Protective Agents; D012333:RNA, Messenger; D050796:STAT3 Transcription Factor; C494088:Stat3 protein, rat; D020032:Tyrphostins; C095512:alpha-cyano-(3,4-dihydroxy)-N-benzylcinnamide; D008668:Metallothionein; C040920:isoliquiritigenin; D007770:L-Lactate Dehydrogenase; D011505:Protein-Tyrosine Kinases; C507927:Jak2 protein, rat; D053614:Janus Kinase 2; D003402:Creatine Kinase