(Circulation. 2000;102:3046.)
© 2000 American Heart Association, Inc.
Clinical Investigation and Reports |
Decreased SLIM1 Expression and Increased Gelsolin Expression in Failing Human Hearts Measured by High-Density Oligonucleotide Arrays
From the Department of Molecular Cardiology (J.Y., M.B.), Molecular Biotechnology Core (L.H.), Center for Anesthesiology Research (C.S.M., N.R.D.), Lerner Research Institute, Cleveland, Ohio; Departments of Cardiology (J.B.Y., G.S.F.), Thoracic and Cardiovascular Surgery (P.M.M.), Kaufman Center for Heart Failure, Cleveland Clinic Foundation, Cleveland, Ohio; Department of Physiology and Biophysics (C.S.M., M.B.), School of Medicine, Case Western Reserve University, Cleveland, Ohio; Division of Molecular Cardiovascular Biology (M.A.S., D.F.), Children’s Hospital Medical Center, Cincinnati, Ohio; and Department of Biochemistry and Molecular Biology, Monash University (C.A.M.), Melbourne, Australia.
Correspondence to Meredith Bond, PhD, Department of Molecular Cardiology NB50, Cleveland Clinic Foundation, Cleveland, OH 44195. E-mail bondm{at}ccf.org
Background—Failing human hearts are characterized by altered cytoskeletal and myofibrillar organization, impaired signal transduction, abnormal protein turnover, and impaired energy metabolism. Thus, expression of multiple classes of genes is likely to be altered in human heart failure.
Methods and Results—We
used high-density oligonucleotide arrays to explore changes in
expression of 
7000 genes in 2 nonfailing and 2 failing human hearts
with diagnoses of end-stage ischemic and dilated cardiomyopathy,
respectively. We report altered expression of (1) cytoskeletal and
myofibrillar genes (striated muscle LIM protein-1 [SLIM1], myomesin,
nonsarcomeric myosin regulatory light chain-2
[MLC2], and ß-actin); (2) genes responsible
for degradation and disassembly of myocardial proteins
(
1-antichymotrypsin, ubiquitin, and
gelsolin); (3) genes involved in metabolism (ATP synthase -subunit,
succinate dehydrogenase flavoprotein [SDH Fp] subunit, aldose
reductase, and TIM17 preprotein translocase); (4) genes responsible for
protein synthesis (elongation factor-2 [EF-2], eukaryotic initiation
factor-4AII, and transcription factor homologue-HBZ17); and (5) genes
encoding stress proteins (B-crystallin and µ-crystallin). In 5
additional failing hearts and 4 additional nonfailing controls, we then
compared expression of proteins encoded by the differentially expressed
genes, B-crystallin, SLIM1, gelsolin,
1-antichymotrypsin, and ubiquitin. In each
case, changes in protein expression were consistent with changes in
transcript measured by microarray analysis. Gelsolin protein expression
was also increased in cardiomyopathic hearts from
tropomodulin-overexpressing (TOT) mice and rac1-expressing (racET)
mice.
Conclusions—Altered expression of the genes identified in this study may contribute to development of the heart failure phenotype and/or represent compensatory mechanisms to sustain cardiac function in failing human hearts.
Key Words: heart failure • cardiomyopathy • gene expression
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