Decreased SLIM1 expression and increased gelsolin expression in failing human hearts measured by high-density oligonucleotide arrays

Background-Failing human hearts are characterized by altered cytoskeletal a nd myofibrillar organization, impaired signal transduction, abnormal protei n turnover, and impaired energy metabolism. Thus, expression of multiple cl asses 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 approximate to 7000 genes in 2 nonfailing and 2 fa iling human hearts with diagnoses of end-stage ischemic and dilated cardiom yopathy, respectively. We report altered expression of (1) cytoskeletal and myofibrillar genes (striated muscle LIM protein-1 [SLIM1], myomesin, nonsa rcomeric myosin regulatory light chain-2 [MLC2], and beta -actin); (2) gene s responsible for degradation and disassembly of myocardial proteins (alpha (1)-antichymotrypsin, ubiquitin, and gelsolin); (3) genes involved in meta bolism (ATP synthase alpha -subunit, succinate dehydrogenase flavoprotein [ SDH Fp] subunit, aldose reductase, and TLM17 preprotein translocase); (4) g enes responsible for protein synthesis (elongation factor-2 [EF-2], eukaryo tic initiation factor-4AII, and transcription factor homologue-HBZ17); and (5) genes encoding stress proteins (alphaB-crystallin and mu -crystallin). In 5 additional failing hearts and 4 additional nonfailing controls, we the n compared expression of proteins encoded by the differentially expressed g enes, alphaB-crystallin, SLIMI, gelsolin, alpha (1)-antichymotrypsin, and u biquitin. In each case, changes in protein expression were consistent with changes in transcript measured by microarray analysis. Gelsolin protein exp ression was also increased in cardiomyopathic hearts from tropomodulin-over expressing (TOT) mice and rad-expressing (racET) mice. Conclusions-Altered expression of the genes identified in this study may co ntribute to development of the heart failure phenotype and/or represent com pensatory mechanisms to sustain cardiac function in failing human hearts.