Amino acid supplementation differentially modulates STAT1 and STAT3 activation in the myocardium exposed to ischemia/reperfusion injury.
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.
Scarabelli
Tiziano M
TM
Center for Heart and Vessel Preclinical Studies, St. John Hospital and Medical Center, Wayne State University School of Medicine, Detroit, Michigan, USA.
Townsend
Paul A
PA
Chen Scarabelli
Carol
C
Yuan
Zhaokan
Z
McCauley
Roy B
RB
Di Rezze
Justin
J
Patel
David
D
Putt
Jeff
J
Allebban
Zuhair
Z
Abboud
John
J
Chilukuri
Karuna
K
Gardin
Julius
J
Saravolatz
Louis
L
Knight
Richard A
RA
Latchman
David S
DS
Stephanou
Anastasis
A
D000596:Amino Acids / Q000008:administration & dosage*; D000818:Animals; D017209:Apoptosis / Q000502:physiology; D019587:Dietary Supplements; D004791:Enzyme Inhibitors / Q000494:pharmacology; D066298:In Vitro Techniques; D008297:Male; D009206:Myocardium / Q000378:metabolism*; D032383:Myocytes, Cardiac / Q000502:physiology; D010766:Phosphorylation; D051381:Rats; D017207:Rats, Sprague-Dawley; D015427:Reperfusion Injury / Q000378:metabolism*; D050794:STAT1 Transcription Factor / Q000378:metabolism*; D050795:STAT2 Transcription Factor / Q000378:metabolism*; D020032:Tyrphostins / Q000494:pharmacology
D000596:Amino Acids; D004791:Enzyme Inhibitors; D050794:STAT1 Transcription Factor; D050795:STAT2 Transcription Factor; C494081:Stat1 protein, rat; D020032:Tyrphostins; C095512:alpha-cyano-(3,4-dihydroxy)-N-benzylcinnamide