© 2003 by European Society of Cardiology
Copyright © 2003, European Society of Cardiology
Activation of signal transducer and activator of transcription (STAT) pathways in failing human hearts
aCell Signalling Laboratory, Biochemistry and Molecular Biology in the School of Biomedical and Chemical Sciences, University of Western Australia, 35 Stirling Highway, Crawley, WA 6009, Australia
bMuscle Research Unit, Institute for Biomedical Research, Department of Anatomy and Histology, University of Sydney, Sydney, NSW, Australia
cWestern Australian Institute for Medical Research, Perth, WA, Australia
* Corresponding author. Tel.: +61-8-9380-1348; fax: +61-8-9380-1148. marieb{at}cyllene.uwa.edu.au
Objectives: The signal transduction pathways mediating the progression to failure have been intensively studied in a variety of in vitro and in vivo animal models. Recently, acute activation of the Janus kinases (JAKs) and signal transducers and activators of transcription (STATs) has been observed in the heart, but whether this is sustained in ischemic heart disease (IHD) or dilated cardiomyopathy (DCM) has not been previously addressed. Methods: We assessed the tyrosine phosphorylation of STAT1, 3, 5 and 6 in ventricular samples of explanted human hearts with IHD (n=11) and DCM (n=9) as an indication of STAT activation. Samples from normal donor hearts (n=9) acted as controls. In parallel, we also assessed protein expression and phosphorylation of three major families of mitogen-activated protein kinases (MAPKs); ERK, p38 MAPK and c-Jun NH2-terminal kinase (JNK). Results: All STAT isoforms were significantly phosphorylated in DCM. In contrast, only the phosphorylation of STATs 1 and 5 were significantly enhanced in IHD. Expression of total STAT protein remained unchanged. For the MAPKs, significant phosphorylation of p38MAPK was only observed in IHD. In contrast, there was no change in ERK or JNK activation despite abundant protein expression. Conclusions: We have shown that different members of the STAT transcription factor family are chronically phosphorylated in the failing heart as a result of IHD (STAT1 and 5) or DCM (STAT1, 3, 5 and 6). In contrast, IHD but not DCM showed significant p38MAPK phosphorylation. Whilst the differences noted between IHD and DCM may reflect different initiating events, the common activation of STATs 1 and 5 suggests that these transcription factors may play a common role regulating the progression of heart failure.
KEYWORDS Cardiomyopathy; Heart failure; Ischemia; Protein phosphorylation; Signal transduction
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