Role of the NF-kappaB signaling cascade and NF-kappaB-targeted genes in failing human hearts.
Nuclear factor-kappaB (NF-kappaB) is a ubiquitous transcription factor that has been indicated to play a causal role for many pathological states. Heart failure is a major cause of morbidity all over the world. In this study, we examined the role of NF-kappaB in failing (F) human hearts and nonfailing (NF) controls. Our data showed that an enhanced activation of this nuclear factor occurs in the F hearts along with its components, like I-kappaB kinase (IKK)beta and IkappaBalpha, both at transcript and translational levels. To obtain a profile of NF-kappaB-targeted gene expression in F hearts, we profiled, for the first time, the expression analysis of NF-kappaB-linked gene using a TranSignal human NF-kappaB-targeted gene array. Our data suggest that more than 50 genes were consistently upregulated in F hearts more than 1.5-fold (vs NF hearts, p<0.001). Our studies demonstrated that NF-kappaB is specifically and significantly activated via IKKbeta in F hearts. The most intriguing aspects of our studies are molecular profiles of NF-kappaB-linked or targeted gene expression in F hearts. Our data suggest that the regulation and control of NF-kappaB activation is, therefore, a powerful therapeutic strategy for delaying or attenuating such deadly disease.
Gupta
Sudhiranjan
S
Department of Molecular Cardiology, NB 50, Cleveland Clinic Foundation, 9500 Euclid Avenue, Cleveland, OH 44195, USA. sens@ccf.org
Sen
Subha
S
D000328:Adult; D000368:Aged; D001345:Autoradiography; D015152:Blotting, Northern; D015153:Blotting, Western; D003720:Densitometry; D024202:Electrophoretic Mobility Shift Assay; D005260:Female; D016650:Fluorescein-5-isothiocyanate; D005456:Fluorescent Dyes; D020869:Gene Expression Profiling; D018390:Gene Targeting; D006333:Heart Failure / Q000235:genetics* / Q000378:metabolism*; D006801:Humans; D020672:I-kappa B Proteins / Q000235:genetics / Q000378:metabolism; D008297:Male; D018613:Microscopy, Confocal; D008875:Middle Aged; D016328:NF-kappa B / Q000235:genetics* / Q000378:metabolism*; D020411:Oligonucleotide Array Sequence Analysis; D015398:Signal Transduction
D005456:Fluorescent Dyes; D020672:I-kappa B Proteins; D016328:NF-kappa B; D016650:Fluorescein-5-isothiocyanate