Activation of signal transducer and activator of transcription (STAT) pathways in failing human hearts.
OBJECTIVE
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 NH(2)-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 p38(MAPK) 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 p38(MAPK) 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.
Ng
Dominic C H
DC
Cell 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.
Court
Naomi W
NW
dos Remedios
Cristobal G
CG
Bogoyevitch
Marie A
MA
D000293:Adolescent; D000328:Adult; D002311:Cardiomyopathy, Dilated / Q000378:metabolism / Q000503:physiopathology; D004268:DNA-Binding Proteins / Q000378:metabolism; D018450:Disease Progression; D005260:Female; D006333:Heart Failure / Q000378:metabolism / Q000503:physiopathology*; D006801:Humans; D008297:Male; D008875:Middle Aged; D020928:Mitogen-Activated Protein Kinases / Q000378:metabolism; D017202:Myocardial Ischemia / Q000378:metabolism / Q000503:physiopathology; D010766:Phosphorylation; D050794:STAT1 Transcription Factor; D050796:STAT3 Transcription Factor; D015398:Signal Transduction; D015534:Trans-Activators / Q000378:metabolism*; D015533:Transcriptional Activation; D048051:p38 Mitogen-Activated Protein Kinases
D004268:DNA-Binding Proteins; D050794:STAT1 Transcription Factor; C494079:STAT1 protein, human; D050796:STAT3 Transcription Factor; C494086:STAT3 protein, human; D015534:Trans-Activators; D020928:Mitogen-Activated Protein Kinases; D048051:p38 Mitogen-Activated Protein Kinases