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J Am Coll Cardiol, 2001; 38:1175-1180
© 2001 by the American College of Cardiology Foundation
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CLINICAL STUDY

Expression profiling of cardiac genes in human hypertrophic cardiomyopathy: insight into the pathogenesis of phenotypes

Do-Sun Lim, MDa, Robert Roberts, MD, FACCa and Ali J. Marian, MD, FACCa

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.

Abbreviations and Acronyms
  ACTA1 = skeletal muscle alpha-actin
  cDNA = complementary deoxyribonucleic acid
  FHL1 = four-and-a-half LIM domain protein 1
  GNAS1 = guanosine 5'-triphosphate (GTP)-binding protein Gs-alpha subunit
  HCM = hypertrophic cardiomyopathy
  HSPA8 = heat shock 70kD protein 8
  MLC2a = myosin light chain 2A
  mRNA = messenger ribonucleic acid
  NDUFB10 = reduced nicotinamide adenine dinucleotide ubiquinone oxidoreductase
  PCR = polymerase chain reaction
  SARCOSIN = sarcosin
  VDAC1 = voltage-dependent anion channel 1




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