Biochemical pathways analysis of intracellular and extracellular signaling in failing human ventricular myocytes: differential signal transducers and activators of transcription (STAT) proteins modulation.

Cardiovascular disease remains the number one cause of mortality in the Western world, with heart failure representing the fastest growing subclass over the past decade. Although signal-transduction pathways are inherently complex and abundant, studies in animal models have revealed important mediators of cardiac hypertrophy from proteins; in particular, recent reports have shown that the JAK-STAT intracellular signal transduction pathway plays a central role in cardiac pathophysiology. Angiotensin II (Ang II)-induced extracellular signal-regulated kinase (ERK)1/2 phosphorylation is reduced in human ventricular failing cardiomyocytes (FM), whereas Janus-activated kinase (JAK)2 phosphorylation is enhanced as compared to non-failing myocardial cells (NFM). Although Ang II-induced JAK2 phosphorylation was reported to be enhanced in failing human cardiomyocytes, the downstream balance between cardio-protective signal transducer and activator of transcription (STAT) 3 and the pro-inflammatory (STAT2 and STAT5) response remains unexplored. Therefore STATs phosphorylation following JAK2 activation were investigated in isolated cardiomyocytes obtained from failing human hearts (n=16), and from non-failing (NF) hearts from humans (putative donors, n=6) or adult rats. In NF myocytes JAK2 activation was followed by STAT3 phosphorylation (205%±43% at 30 min) with no STAT2 or STAT5 response. Conversely in failing myocytes STAT2 (229%±36%) and STAT5 (224%±44%) phosphorylation responses were observed with no STAT3 response. STAT activation was blunted by AT1 but not AT2 antagonism. According to the present findings, an opposite pattern of STAT response characterises FM as compared to NFM. The altered JAK2 induced STATs response in human failing cardiomyocytes, as well as the relative role of glucose, may be of relevance for myocardial hypertrophy in diabetics and the further progression of heart failure due to the selective activity of the STATs involved.