The JAK/STAT pathway is essential for opioid-induced cardioprotection: JAK2 as a mediator of STAT3, Akt, and GSK-3β

Abstract

We examined the role for the JAK/STAT signaling pathway in acute opioid-induced cardioprotection (OIC) and whether opioid-induced glycogen synthase kinase-3beta (GSK-3 beta) inhibition is mediated by the JAK/STAT pathway. Rats underwent 30 min of ischemia and either 5 min or 2 h of reperfusion, followed by tissue isolation for molecular analysis or infarct size assessment, respectively. Rats were treated with vehicle, morphine (300 microg/kg), the delta-opioid agonist fentanyl isothiocynate (FIT, 10 microg/kg), or the GSK inhibitor SB-216763 (SB21, 600 microg/kg) 10 min before ischemia. Five minutes before opioid or SB21 treatment, some rats received the putative JAK2 inhibitor AG-490 (3 mg/kg) or the putative JAK3 inhibitor ZM-449829 (3 mg/kg). H9C2 cardiomyoblast cells were also used to investigate FIT-induced signaling (1 microM) 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 with vehicle (water) when administered before ischemia [43.0 +/- 2.8, 39.1 +/- 3.1, and 42.1 +/- 2.5 (*P < 0.001, respectively) vs. 58.1 +/- 1.3%, respectively]. AG-490 abrogated OIC, whereas ZM-449829 had no effect on OIC. Cardioprotection was afforded by SB21 even in the presence of AG-490. Morphine phosphorylated STAT3, Akt, and GSK-3beta, and phosphorylation was abrogated by AG-490. FIT stimulation of H9C2 cells also caused a time-dependent phosphorylation of STAT3, Akt, and GSK-3beta, and this effect was abrogated by AG-490. STAT3 phosphorylation was also dependent on phosphatidylinositol 3-kinase (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 GSK-3 beta, with GSK-3 beta contributing a central role in acute OIC.

Signal transducer and activator of transcription 3 is involved in the cardioprotective signalling pathway activated by insulin therapy at reperfusion

“…Previous studies have implicated molecular cross-talk between JAK/STAT and PI3K pathways in nonmyocardial cells activated by luteinizing hormone or carbon monoxide [3,49] and in myocardial cells activated by opioids [13]. Furthermore, coupling of PI3K to the interferon surface receptor-1 through STAT3 has been reported [34].…”

“…The Janus activated kinase (JAK) and Signal Transducer and Activator of Transcription 3 (STAT3) signalling pathway is responsive to a large number of cytokines, growth factors and hormones [6,7,18], and is known to play a vital role in cardioprotection related to ischemia-reperfusion (I/R) injury [2,13,16,24,26,28,29,39,46]. This pathway is activated by a diversity of receptors, including receptor tyrosine kinases [38,45,51] and Gprotein-coupled receptors [11,33].…”

Mu Opioid Signaling Protects Against Acute Murine Intestinal Injury in a Manner Involving Stat3 Signaling

“…[13][14][15] Interestingly, recent studies have shown opioids to protect against ischemia/reperfusion-induced cardiac injury. 16,17 Furthermore, the peripheral mu-specific agonist [D-Arg2,Lys4]dermorphin-(1,4)-amide (DALDA) 18 reduces inflammation in two experimental models of murine colitis: 2,4,6-trinitrobenzene sulfonic acid (TNBS) and adoptive transfer of CD45RB hi CD4 ϩ T cells. 19 Conversely, experimental colitis is exacerbated in mu opioid receptor (MOR) knockout mice, 19 and MOR expression is up-regulated in mucosal samples from human patients with IBD compared with controls.…”

“…On the basis of its beneficial effect in other models of colitis, 19 as well as in ischemia-induced cardiac injury, 16,17 we hypothesized that MOR signaling is cytoprotective in the context of intestinal barrier damage. With the use of a chemical model of acute injury and wound healing that is independent of T and B cells, 21 we observed that the mu opioid agonist DALDA protects against dextran sodium sulfate (DSS)-induced intestinal injury and promotes healing through activation of Stat3 and induction of cytoprotective factors regulated in part by Stat3.…”

Cardioplegia and Diazoxide Modulate STAT3 Activation and DNA Binding

“…Previous reports have shown that c-Jun interacts with STAT3 and enhances STAT3 DNA-binding [19][20][21][22][23]. In this report, we attempted to examine whether c-Jun interacts with STAT3 in our model by coimmunoprecipitation with anti-STAT3 antibodies followed by Western blot analysis with anti-c-Jun antibodies.…”