Aldose reductase pathway mediates JAK-STAT signaling: a novel axis in myocardial ischemic injury.
The aldose reductase pathway has been demonstrated to be a key component of myocardial ischemia reperfusion injury. Previously, we demonstrated that increased lactate/pyruvate ratio, a measure of cytosolic NADH/NAD+, is an important change that drives the metabolic cascade mediating ischemic injury. This study investigated signaling mechanisms by which the aldose reductase pathway mediates myocardial ischemic injury. Specifically, the influence of the aldose reductase pathway flux on JAK-STAT signaling was examined in perfused hearts. Induction of global ischemia in rats resulted in JAK2 activation followed by STAT5 activation. Pharmacological inhibition of aldose reductase or sorbitol dehydrogenase blocked JAK2 and STAT5 activation and was associated with lower lactate/pyruvate ratio and lower protein kinase C activity. Niacin, known to lower cytosolic NADH/NAD+ ratio independent of the aldose reductase pathway inhibition, also blocked JAK2 and STAT5 activation. Inhibition of protein kinase C also blocked JAK2 and STAT5 activation. Transgenic mice overexpressing human aldose reductase exhibited increased JAK2 and STAT5 activation. Pharmacological inhibition of JAK2 reduced ischemic injury and improved functional recovery similar to that observed in aldose reductase pathway inhibited mice hearts. These data, for the first time, demonstrate JAK-STAT signaling by the aldose reductase pathway in ischemic hearts and is, in part, due to changes in cytosolic redox state.
Hwang
Yuying C
YC
Division of Surgical Science, Department of Surgery, College of Physicians and Surgeons, Columbia University, New York, New York 10032, USA.
Shaw
Sean
S
Kaneko
Michiyo
M
Redd
Heather
H
Marrero
Mario B
MB
Ramasamy
Ravichandran
R
D000449:Aldehyde Reductase / Q000037:antagonists & inhibitors / Q000235:genetics / Q000502:physiology*; D000818:Animals; D015153:Blotting, Western; D004789:Enzyme Activation / Q000187:drug effects; D004791:Enzyme Inhibitors / Q000494:pharmacology; D006801:Humans; D053614:Janus Kinase 2; D007064:L-Iditol 2-Dehydrogenase / Q000037:antagonists & inhibitors / Q000378:metabolism; D019344:Lactic Acid / Q000032:analysis; D051379:Mice; D008810:Mice, Inbred C57BL; D008822:Mice, Transgenic; D017202:Myocardial Ischemia / Q000201:enzymology*; D009206:Myocardium / Q000737:chemistry; D009525:Niacin / Q000494:pharmacology; D010084:Oxidation-Reduction; D010766:Phosphorylation; D011493:Protein Kinase C / Q000378:metabolism; D011505:Protein-Tyrosine Kinases / Q000032:analysis / Q000037:antagonists & inhibitors / Q000378:metabolism*; D011518:Proto-Oncogene Proteins / Q000032:analysis / Q000037:antagonists & inhibitors / Q000378:metabolism*; D019289:Pyruvic Acid / Q000032:analysis; D051381:Rats; D017208:Rats, Wistar; D050799:STAT5 Transcription Factor / Q000032:analysis / Q000037:antagonists & inhibitors / Q000378:metabolism*; D015398:Signal Transduction / Q000502:physiology*
D004791:Enzyme Inhibitors; D011518:Proto-Oncogene Proteins; D050799:STAT5 Transcription Factor; D009525:Niacin; D019344:Lactic Acid; D019289:Pyruvic Acid; D007064:L-Iditol 2-Dehydrogenase; D000449:Aldehyde Reductase; D011505:Protein-Tyrosine Kinases; C507924:JAK2 protein, human; C507926:Jak2 protein, mouse; C507927:Jak2 protein, rat; D053614:Janus Kinase 2; D011493:Protein Kinase C