Amino acid supplementation differentially modulates STAT1 and STAT3 activation in the myocardium exposed to ischemia/reperfusion injury

Scarabelli, Tiziano M., Townsend, Paul A., Chen Scarabelli, Carol, Yuan, Zhaokan, McCauley, Roy B., Di Rezze, Justin, Patel, David, Putt, Jeff, Allebban, Zuhair, Abboud, John, Chilukuri, Karuna, Gardin, Julius, Saravolatz, Louis, Knight, Rrichard A., Latchman, David S. and Stephanou, Anastasis (2008) Amino acid supplementation differentially modulates STAT1 and STAT3 activation in the myocardium exposed to ischemia/reperfusion injury. The American Journal of Cardiology, 101 (11A), 63E-68E. (doi:10.1016/j.amjcard.2008.03.003).

Abstract

We have previously demonstrated that the transcription factor STAT1 plays a critical role in promoting apoptotic cell death, whereas the related STAT3 family member may antagonize STAT1 and protect cardiac myocytes from ischemia/reperfusion (I/R) injury. More recently we demonstrated that long-term nutritional supplementation with mixed amino acids (AAs) can enhance myocyte survival by preserving mitochondrial functional capacity during I/R injury. We therefore investigated whether short-term nutritional supplementation with the same AA mixture has any effects on STAT1 or STAT3 activation in the Langendorff perfused rat heart exposed to I/R injury. In Sprague-Dawley rats given a single oral dose of a mixture of mainly essential l-AA (1 g/kg), and exposed, after 6 hours, to 35 minutes of ischemia, followed by 120 minutes of reperfusion, AA supplementation prolonged STAT3 activation/phosphorylation, while STAT1 activation was reduced. Enhanced STAT3 phosphorylation paralleled a reduction in expression of Fas, a known STAT1 target gene and proapoptotic marker that is upregulated after I/R. Moreover, abrogation of STAT3 activation by means of the JAK inhibitor AG490, reduced, but did not abolish, the cardioprotective effects of AA supplementation after I/R. These results show that modulation of the functional balance between STAT3 and STAT1, with preferential activation of prosurvival STAT3 over the proapoptotic STAT1, represents a mechanism by means of which short-term oral supplementation with mixed AAs protects the heart from I/R injury

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