Abstract
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.
Publication types
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Research Support, U.S. Gov't, P.H.S.
MeSH terms
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Adult
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Aged
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Antigens, Differentiation / genetics
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Apoptosis / physiology*
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CASP8 and FADD-Like Apoptosis Regulating Protein
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Cardiac Output, Low / genetics
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Cardiac Output, Low / metabolism
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Cardiac Output, Low / physiopathology*
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Cardiomyopathy, Dilated / genetics
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Cardiomyopathy, Dilated / metabolism
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Cardiomyopathy, Dilated / physiopathology*
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Carrier Proteins / genetics
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Carrier Proteins / metabolism
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DNA-Binding Proteins
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Disease Progression
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Female
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Gene Expression
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Humans
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Intracellular Signaling Peptides and Proteins*
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Male
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Middle Aged
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NF-kappa B / metabolism
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Nuclear Proteins
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Oligonucleotide Array Sequence Analysis
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Phosphorylation
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Proteins / genetics
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Signal Transduction / physiology*
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Tumor Necrosis Factor alpha-Induced Protein 3
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Tumor Necrosis Factor-alpha / metabolism
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bcl-Associated Death Protein
Substances
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Antigens, Differentiation
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BAD protein, human
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CASP8 and FADD-Like Apoptosis Regulating Protein
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CFLAR protein, human
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Carrier Proteins
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DNA-Binding Proteins
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GADD45B protein, human
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Intracellular Signaling Peptides and Proteins
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NF-kappa B
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Nuclear Proteins
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Proteins
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Tumor Necrosis Factor-alpha
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bcl-Associated Death Protein
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TNFAIP3 protein, human
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Tumor Necrosis Factor alpha-Induced Protein 3