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.