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Regulating RISK: a role for JAK-STAT signaling in postconditioning?
Michael D Goodman1, Sheryl E Koch, Geraldine A Fuller-Bicer
1Department of Surgery, University of Cincinnati, Cincinnati, Ohio 45267, USA. goodmamd@email.uc.edu
American Journal of Physiology. Heart and Circulatory Physiology
|August 19, 2008
Summary
Postconditioning (POC) protects the heart by activating survival pathways. While JAK-STAT signaling is involved, it requires PI3K-Akt activation for effective cardioprotection against ischemia-reperfusion injury.
Area of Science:
- Cardiovascular Physiology
- Molecular Cardiology
- Cellular Signaling
Background:
- Postconditioning (POC) is a promising cardioprotective strategy applied during reperfusion to mitigate ischemia-reperfusion injury.
- POC activates key intracellular survival pathways, notably the phosphatidylinositol 3-kinase (PI3K)-Akt (RISK) pathway.
- The upstream regulators of POC-induced RISK pathway activation remain incompletely understood, with JAK-STAT signaling implicated in cardiac ischemic tolerance.
Purpose of the Study:
- To investigate the hypothesis that POC-mediated cardioprotection necessitates the activation of both JAK-STAT and RISK signaling pathways.
- To elucidate the specific roles of JAK-STAT and PI3K-Akt signaling in mediating the protective effects of POC.
Main Methods:
- Langendorff-perfused mouse hearts subjected to global ischemia and reperfusion with or without POC.
- Pharmacological inhibition of JAK2 (AG 490), STAT3 (Stattic), or PI3K (LY-294002) during reperfusion in POC hearts.
- Assessment of myocardial function and analysis of phosphorylated STAT3 and Akt expression via Western immunoblotting.
- Evaluation of POC effects in cardiomyocyte-specific STAT3 knockout (KO) mouse hearts.
Main Results:
- POC significantly improved myocardial functional recovery and increased the expression of phosphorylated STAT3 and Akt.
- Inhibition of JAK-STAT signaling abrogated POC-induced functional protection.
- STAT3 inhibition reduced both phosphorylated STAT3 and Akt levels, while PI3K inhibition attenuated cardioprotection and reduced phosphorylated Akt but did not affect STAT3 phosphorylation.
- STAT3 knockout hearts subjected to POC demonstrated enhanced ischemic tolerance compared to non-POC controls.
Conclusions:
- Postconditioning induces cardioprotection through activation of the RISK pathway.
- JAK-STAT signaling is essential for effective POC, but its protective effects are contingent upon concurrent PI3K-Akt activation.
- These findings highlight a crucial interplay between JAK-STAT and PI3K-Akt pathways in mediating POC-induced cardioprotection.
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