, Volume 103, Issue 5, pp 444-453

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

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Abstract

Objective

To evaluate the significance of the JAK-STAT pathway in insulin-induced cardioprotection from reperfusion injury.

Methods

In isolated perfused rat hearts subjected to insulin therapy (0.3 mU/ml) ± AG490 (5 µM, JAK-STAT inhibitor), the phosphorylation state of STAT3 and Akt was determined after 15 min of reperfusion. Infarct size was measured after 120 min of reperfusion. Isolated cardiac myocytes from wild type (WT) and cardiac specific STAT3 deficient mice were treated with insulin at reoxygenation following simulated ischemia (SI, 26 h). Cell viability was measured after 120 min of reoxygenation following SI, whereas phosphorylation state of Akt was measured after 15 min of reoxygenation following SI.

Results

Insulin given at reperfusion led to phosphorylation of STAT3 and Akt both of which were inhibited by AG490. AG490 also blocked the insulin-dependent decrease in infarct size, supporting a role for JAK-STAT in cardioprotection. In addition, insulin protection from SI was blocked in myocytes from the STAT3 deficient mice, or in WT mice treated with AG490. Furthermore, insulin failed to phosphorylate Akt in the STAT3 deficient cardiomyocytes.

Conclusion

Insulin-induced cardioprotection at reperfusion occurs through activation of STAT3. Inhibiting STAT3 by AG490, or STAT3 depletion in cardiac myocytes affects activation of Akt, suggesting close interaction between STAT3 and Akt in the cardioprotective signalling pathway activated by insulin treatment at reperfusion.

Returned for 1. Revision: 7 January 2008 1. Revision received: 31 March 2008
Returned for 2. Revision: 15 April 2008 2. Revision received: 18 April 2008
Britt N. Fuglesteg and Naushaad Suleman contributed equally to this work.