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J Am Coll Cardiol, 2001; 38:1175-1180 © 2001 by the American College of Cardiology Foundation |
a Section of Cardiology, Department of Medicine, Baylor College of Medicine, Houston, Texas, USA
Manuscript received January 31, 2001; revised manuscript received June 11, 2001, accepted June 26, 2001.
Reprint requests and correspondence: Dr. A. J. Marian, Section of Cardiology, Baylor College of Medicine, One Baylor Plaza, 543E, Houston, Texas 77030
amarian{at}bcm.tmc.edu
OBJECTIVES
The goal of this study was to identify genes upregulated in the heart in human patients with hypertrophic cardiomyopathy (HCM).
BACKGROUND
Hypertrophic cardiomyopathy is a genetic disease caused by mutations in contractile sarcomeric proteins. The molecular basis of diverse clinical and pathologic phenotypes in HCM remains unknown.
METHODS
We performed polymerase chain reaction-select complementary DNA subtraction between normal hearts and hearts with HCM and screened subtracted libraries by Southern blotting. We sequenced the differentially expressed clones and performed Northern blotting to detect increased expression levels.
RESULTS
We screened 288 independent clones, and 76 clones had less than twofold increase in the signal intensity and were considered upregulated. Sequence analysis identified 36 genes including those encoding the markers of pressure overload-induced ("secondary") cardiac hypertrophy, cytoskeletal proteins, protein synthesis, redox system, ion channels and those with unknown function. Northern blotting confirmed increased expression of skeletal muscle alpha-actin (ACTA1), myosin light chain 2a (MLC2a), GTP-binding protein Gs-alpha subunit (GNAS1), NADH ubiquinone oxidoreductase (NDUFB10), voltage-dependent anion channel 1 (VDAC1), four-and-a-half LIM domain protein 1 (FHL1) (also known as SLIM1), sarcosin (SARCOSIN) and heat shock 70kD protein 8 (HSPA8) by less than twofold. Expression levels of ACTA1, MLC2a and GNAS1 were increased in six additional and FHL1 in four additional hearts with HCM.
CONCLUSIONS
A diverse array of genes is upregulated in the heart in human patients with HCM, which could account for the diversity of clinical and pathologic phenotypes. Markers of secondary hypertrophy are also upregulated, suggesting commonality of pathways involved in HCM and the acquired forms of cardiac hypertrophy. Elucidation of the role of differentially expressed genes in HCM could provide for new therapeutic targets.
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