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Am J Physiol Heart Circ Physiol (March 3, 2006). doi:10.1152/ajpheart.00003.2006
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Submitted on January 3, 2006
Accepted on February 23, 2006

The JAK/STAT Pathway is Essential For Opioid-Induced Cardioprotection: JAK2 as a Mediator of STAT3, Akt and GSK3{beta}

Eric R Gross1, Anna K Hsu1, and Garrett J Gross1*

1 Department of Pharmacology and Toxicology, Medical College of Wisconsin, Milwaukee, WI, USA

* To whom correspondence should be addressed. E-mail: ggross{at}mcw.edu.

We examined the role for the JAK/STAT signaling pathway in opioid-induced acute cardioprotection (OIC) and whether opioid-induced GSK3{beta} inhibition is mediated by the JAK/STAT pathway. Rats underwent 30 min of ischemia and either 5 minutes or 2 hrs of reperfusion, followed by tissue isolation for molecular analysis or infarct size assessment, respectively. Rats were treated with vehicle, morphine (300µg/kg), the {delta}opioid agonist FIT (10µg/kg), or the GSK inhibitor, SB216763 (SB21, 600µg/kg) 10 minutes before ischemia. Five minutes before opioid or SB216763 treatment, some rats received the putative JAK2 inhibitor, AG490(3mg/kg), or the putative JAK3 inhibitor, ZM449829(3mg/kg). H9C2 cardiomyoblast cells were also used to investigate FIT-induced signaling (1µM) in vitro via molecular analysis. Morphine induced the phosphorylation of JAK2, yet not JAK1 in the area at risk. Morphine, FIT and SB21 also reduced infarct size compared to vehicle (water) when administered prior to ischemia (43.0±2.8*, 39.1±3.1*, 42.1±2.5* vs 58.1±1.3% respectively, *P<0.001). AG490 abrogated OIC, while ZM449829 had no effect on OIC. Cardioprotection was afforded by SB21 even in the presence of AG490. Morphine phosphorylated STAT3, Akt and GSK3{beta} and phosphorylation was abrogated by AG490. FIT stimulation of H9C2 cells also caused a time-dependent phosphorylation of STAT3, Akt and GSK3{beta}, and this effect was abrogated by AG490. STAT3 phosphorylation was also dependent upon PI3k activation in both tissue and H9C2 cells. These data suggest that OIC occurs via the JAK2 regulation of PI3k pathway dependent STAT3, Akt and GSK3{beta}, with GSK3{beta} contributing a central role in acute OIC.




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