Alterations in apoptotic signaling in human idiopathic cardiomyopathic hearts in failure.
Dilated cardiomyopathy, a disease of unknown etiology and pathogenesis, is associated with heart failure and compensatory hypertrophy. Although cell and animal models suggest a role for altered gene expression in the transition to heart failure, there is a paucity of data derived from the study of human heart tissue. In this study, we used DNA microarray profiling to investigate changes in the expression of genes involved in apoptosis that occur in human idiopathic dilated cardiomyopathic hearts that had progressed to heart failure. We observed altered gene expression consistent with a proapoptotic shift in the TNF-alpha signaling pathway. Specifically, we found decreased expression of TNF-alpha- and NF-kappaB-induced antiapoptotic genes such as growth arrest and DNA damage-inducible (GADD)45beta, Flice inhibitory protein (FLIP), and TNF-induced protein 3 (A20). Consistent with a role for apoptosis in heart failure, we also observed a significant decrease in phosphorylation of BAD at Ser-112. This study identifies several pathways that are altered in human heart failure and provides new targets for therapy.
Steenbergen
Charles
C
Department of Pathology, Duke University Medical Center, Durham 27710, USA.
Afshari
Cynthia A
CA
Petranka
John G
JG
Collins
Jennifer
J
Martin
Karla
K
Bennett
Lee
L
Haugen
Astrid
A
Bushel
Pierre
P
Murphy
Elizabeth
E
D000328:Adult; D000368:Aged; D000943:Antigens, Differentiation / Q000235:genetics; D017209:Apoptosis / Q000502:physiology*; D053446:CASP8 and FADD-Like Apoptosis Regulating Protein; D002303:Cardiac Output, Low / Q000235:genetics / Q000378:metabolism / Q000503:physiopathology*; D002311:Cardiomyopathy, Dilated / Q000235:genetics / Q000378:metabolism / Q000503:physiopathology*; D002352:Carrier Proteins / Q000235:genetics / Q000378:metabolism; D004268:DNA-Binding Proteins; D018450:Disease Progression; D005260:Female; D015870:Gene Expression; D006801:Humans; D047908:Intracellular Signaling Peptides and Proteins; D008297:Male; D008875:Middle Aged; D016328:NF-kappa B / Q000378:metabolism; D009687:Nuclear Proteins; D020411:Oligonucleotide Array Sequence Analysis; D010766:Phosphorylation; D011506:Proteins / Q000235:genetics; D015398:Signal Transduction / Q000502:physiology*; D000072598:Tumor Necrosis Factor alpha-Induced Protein 3; D014409:Tumor Necrosis Factor-alpha / Q000378:metabolism; D051025:bcl-Associated Death Protein; D000097642:GADD45 Proteins
D000943:Antigens, Differentiation; D053446:CASP8 and FADD-Like Apoptosis Regulating Protein; D002352:Carrier Proteins; D004268:DNA-Binding Proteins; D047908:Intracellular Signaling Peptides and Proteins; D016328:NF-kappa B; D009687:Nuclear Proteins; D011506:Proteins; D000072598:Tumor Necrosis Factor alpha-Induced Protein 3; D014409:Tumor Necrosis Factor-alpha; D051025:bcl-Associated Death Protein; C494819:BAD protein, human; C506386:CFLAR protein, human; C086470:GADD45B protein, human; D000097642:GADD45 Proteins; C076529:TNFAIP3 protein, human