Janus kinase-2 signaling mediates apoptosis in rat cardiomyocytes.
We tested the hypothesis that activation Jak2, which is prominently involved in the up-regulation of the renin-angiotensin system (RAS), constitutes a focal point in relaying signals triggered by a Angiotensin II (Ang II) and hypoxia/reoxygenation separately to cause an enhanced susceptibility of cardiac myocyte to apoptotic cell death. Ang II-treated adult cardiomyocytes in culture exhibited an increased level of apoptosis that accompanied activation of pro-apoptotic as well as anti-apoptotic signaling pathways. We observed increased phosphorylation of Jak2 kinase, Stat1, JNK, with increased expression of Bax protein, followed by an increase in caspase-1 and caspase-3 activity. Activation of these pro-apoptotic pathways was blocked by the Jak2 pharmacological inhibitor, Tyrphostin AG490. We also observed an increase in phosphorylation of cardioprotective pathway components, namely S6 ribosomal protein, and heat shock protein 27 (HSP27). Likewise, the oxidative stress, via the hypoxia/reoxygenation treatment of rat adult cardiomyocytes, produced apoptosis that was dependent upon activation of Jak2. The apoptotic response was not only reduced by Losartan, an inverse agonist of the AT1, receptor, but by treatment with AG490 as well. Taken together, these observations provide clear evidence in favor of Jak2 signaling as mediator of the apoptotic response in cardiomyocytes. However, there was a concomitant induction of cytoprotective signaling that presumably provides a negative feed-back to the deleterious effects of the agonist.
Mascareno
Eduardo
E
Center for Cardiovascular and Muscle Research, Department of Anatomy and Cell Biology, State University of New York Downstate Medical Center, 450 Clarkson Avenue, Brooklyn, N.Y. 11203, USA.
Beckles
Daniel L
DL
Siddiqui
M A Q
MA
D000804:Angiotensin II / Q000502:physiology; D000818:Animals; D017209:Apoptosis / Q000502:physiology*; D015153:Blotting, Western; D020169:Caspases / Q000032:analysis / Q000378:metabolism; D002460:Cell Line; D002478:Cells, Cultured; D024202:Electrophoretic Mobility Shift Assay; D053614:Janus Kinase 2; D032383:Myocytes, Cardiac / Q000502:physiology*; D010766:Phosphorylation; D011505:Protein-Tyrosine Kinases / Q000235:genetics / Q000502:physiology*; D011518:Proto-Oncogene Proteins / Q000235:genetics / Q000502:physiology*; D051381:Rats; D017207:Rats, Sprague-Dawley; D050794:STAT1 Transcription Factor / Q000502:physiology; D050796:STAT3 Transcription Factor / Q000502:physiology; D015398:Signal Transduction / Q000502:physiology*; D014162:Transfection; D014443:Tyrosine / Q000502:physiology; D051028:bcl-2-Associated X Protein / Q000502:physiology
D011518:Proto-Oncogene Proteins; D050794:STAT1 Transcription Factor; D050796:STAT3 Transcription Factor; D051028:bcl-2-Associated X Protein; D000804:Angiotensin II; D014443:Tyrosine; D011505:Protein-Tyrosine Kinases; C507927:Jak2 protein, rat; D053614:Janus Kinase 2; D020169:Caspases