Impaired JAK2-induced activation of STAT3 in failing human myocytes.
Although angiotensin (Ang)II-induced Janus-activated kinase (JAK)2 phosphorylation was reported to be enhanced in failing human cardiomyocytes, the downstream balance between cardio-protective (signal transducer and activator of transcription-STAT3) and the pro-inflammatory (STAT2 and STAT5) response remains unexplored. Therefore STATs phosphorylation and putative genes overexpression following JAK2 activation were investigated in isolated cardiomyocytes obtained from failing human hearts (n = 16), and from non-failing(NF) hearts of humans (putative donors, n = 6) or adult rats. In NF myocytes Ang II-induced JAK2 activation was followed by STAT3 phosphorylation (186 ± 45% at 30 min), with no STAT2 or STAT5 response. The associated B cell lymphoma (Bcl)-xL overexpression (1.05 ± 0.39 fold) was abolished by both JAK2 and extracellular signal-regulated kinase (ERK)1/2 inhibitors (AG490, 10 μM, and PD98059, 30 μM, respectively), whereas Fas ligand (Fas-L) response (0.91 ± 0.21 fold) was inhibited only by p38MAPK antagonism (SB203580, 10 μM). In failing myocytes Ang II-induced JAK2 activation was followed by STAT2 (237 ± 38%) and STAT5 (222 ± 31%) phosphorylation, with no STAT3 response. No changes in Bcl-xL expression were observed, and the associated Fas-L gene overexpression (1.14 ± 0.27 fold) being abolished by p38 mitogen-activated protein kinase (MAPK) antagonism. The altered JAK2 induced STATs response in human failing cardiomyocytes may be of relevance for the progression of cardiac dysfunction in heart failure.
Department of Critical Care Medicine, University of Florence, Largo Brambilla 3, 50134 Florence, Italy.
Giulia Elisa
GE
Cambi
Gianluca
G
Lucchese
Mah Mc Harol
MM
Djeokeng
Alessandra
A
Modesti
Tania
T
Fiaschi
Giuseppe
G
Faggian
Guido
G
Sani
Pietro Amedeo
PA
Modesti
D000804:Angiotensin II / Q000494:pharmacology; D015153:Blotting, Western; D002478:Cells, Cultured; D004791:Enzyme Inhibitors / Q000494:pharmacology; D006333:Heart Failure / Q000201:enzymology*; D006801:Humans; D015850:Interleukin-6 / Q000494:pharmacology; D053614:Janus Kinase 2 / Q000037:antagonists & inhibitors / Q000378:metabolism*; D032342:Muscle Cells / Q000187:drug effects / Q000378:metabolism*; D010766:Phosphorylation / Q000187:drug effects; D050796:STAT3 Transcription Factor / Q000378:metabolism*; D015398:Signal Transduction / Q000187:drug effects; D020032:Tyrphostins / Q000494:pharmacology
D004791:Enzyme Inhibitors; D015850:Interleukin-6; D050796:STAT3 Transcription Factor; D020032:Tyrphostins; C095512:alpha-cyano-(3,4-dihydroxy)-N-benzylcinnamide; D000804:Angiotensin II; D053614:Janus Kinase 2