Aldose reductase pathway mediates JAK‐STAT signaling: a novel axis in myocardial ischemic injury
| Autor: | Ravichandran Ramasamy, Mario B. Marrero, Michiyo Kaneko, Sean Shaw, Yuying C. Hwang, Heather Redd |
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| Rok vydání: | 2005 |
| Předmět: |
L-Iditol 2-Dehydrogenase
medicine.medical_specialty Cell signaling Sorbitol dehydrogenase Blotting Western Myocardial Ischemia Ischemia Mice Transgenic Biology Niacin Biochemistry Mice chemistry.chemical_compound Aldehyde Reductase Proto-Oncogene Proteins Internal medicine Pyruvic Acid STAT5 Transcription Factor Genetics medicine Animals Humans Lactic Acid Enzyme Inhibitors Phosphorylation Rats Wistar Molecular Biology Protein Kinase C Protein kinase C Aldose reductase Myocardium Janus Kinase 2 Protein-Tyrosine Kinases medicine.disease Rats Enzyme Activation Mice Inbred C57BL Cytosol Endocrinology chemistry Sorbitol NAD+ kinase Oxidation-Reduction Signal Transduction Biotechnology |
| Zdroj: | The FASEB Journal. 19:1-19 |
| ISSN: | 1530-6860 0892-6638 |
| DOI: | 10.1096/fj.04-2780fje |
| Popis: | 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. |
| Databáze: | OpenAIRE |
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