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 |
|
This article has been cited by other articles:
|
|
|
|
 
G. Kwapiszewska, M. Wygrecka, L. M. Marsh, S. Schmitt, R. Trosser, J. Wilhelm, K. Helmus, B. Eul, A. Zakrzewicz, H. A. Ghofrani, et al.
Fhl-1, a New Key Protein in Pulmonary Hypertension
Circulation,
September 9, 2008;
118(11):
1183 - 1194.
[Abstract]
[Full Text]
[PDF]
|
|
|
|
|
|
|
Z. Yang, C. F. Browning, H. Hallaq, L. Yermalitskaya, J. Esker, M. R. Hall, A. J. Link, A.-J. L. Ham, M. J. McGrath, C. A. Mitchell, et al.
Four and a half LIM protein 1: a partner for KCNA5 in human atrium
Cardiovasc Res,
June 1, 2008;
78(3):
449 - 457.
[Abstract]
[Full Text]
[PDF]
|
|
|
|
|
|
|
T. Bupha-Intr, J. W. Holmes, and P. M. L. Janssen
Induction of hypertrophy in vitro by mechanical loading in adult rabbit myocardium
Am J Physiol Heart Circ Physiol,
December 1, 2007;
293(6):
H3759 - H3767.
[Abstract]
[Full Text]
[PDF]
|
|
|
|
|
|
|
M. Xin, E. M. Small, E. van Rooij, X. Qi, J. A. Richardson, D. Srivastava, O. Nakagawa, and E. N. Olson
Essential roles of the bHLH transcription factor Hrt2 in repression of atrial gene expression and maintenance of postnatal cardiac function
PNAS,
May 8, 2007;
104(19):
7975 - 7980.
[Abstract]
[Full Text]
[PDF]
|
|
|
|
|
|
|
D. L. Cottle, M. J. McGrath, B. S. Cowling, I. D. Coghill, S. Brown, and C. A. Mitchell
FHL3 binds MyoD and negatively regulates myotube formation
J. Cell Sci.,
April 15, 2007;
120(8):
1423 - 1435.
[Abstract]
[Full Text]
[PDF]
|
|
|
|
|
|
|
S. Rajan, S. S. Williams, G. Jagatheesan, R. P. H. Ahmed, G. Fuller-Bicer, A. Schwartz, B. J. Aronow, and D. F. Wieczorek
Microarray analysis of gene expression during early stages of mild and severe cardiac hypertrophy
Physiol Genomics,
November 21, 2006;
27(3):
309 - 317.
[Abstract]
[Full Text]
[PDF]
|
|
|
|
|
|
|
E. S. Montana and J. T. Littleton
Expression Profiling of a Hypercontraction-induced Myopathy in Drosophila Suggests a Compensatory Cytoskeletal Remodeling Response
J. Biol. Chem.,
March 24, 2006;
281(12):
8100 - 8109.
[Abstract]
[Full Text]
[PDF]
|
|
|
|
|
|
|
M. J. McGrath, D. L. Cottle, M.-A. Nguyen, J. M. Dyson, I. D. Coghill, P. A. Robinson, M. Holdsworth, B. S. Cowling, E. C. Hardeman, C. A. Mitchell, et al.
Four and a Half LIM Protein 1 Binds Myosin-binding Protein C and Regulates Myosin Filament Formation and Sarcomere Assembly
J. Biol. Chem.,
March 17, 2006;
281(11):
7666 - 7683.
[Abstract]
[Full Text]
[PDF]
|
|
|
|
|
|
|
M. Wellner, R. Dechend, J.-K. Park, E. Shagdarsuren, N. Al-Saadi, T. Kirsch, P. Gratze, W. Schneider, S. Meiners, A. Fiebeler, et al.
Cardiac gene expression profile in rats with terminal heart failure and cachexia
Physiol Genomics,
February 10, 2005;
20(3):
256 - 267.
[Abstract]
[Full Text]
[PDF]
|
|
|
|
|
|
|
A. C. Mistry, A. Kato, Y. H. Tran, S. Honda, T. Tsukada, Y. Takei, and S. Hirose
FHL5, a novel actin-binding protein, is highly expressed in eel gill pillar cells and responds to wall tension
Am J Physiol Regulatory Integrative Comp Physiol,
November 1, 2004;
287(5):
R1141 - R1154.
[Abstract]
[Full Text]
[PDF]
|
|
|
|
|
|
|
V. Gaussin, J. E. Tomlinson, C. Depre, S. Engelhardt, C. L. Antos, G. Takagi, L. Hein, J. N. Topper, S. B. Liggett, E. N. Olson, et al.
Common Genomic Response in Different Mouse Models of {beta}-Adrenergic-Induced Cardiomyopathy
Circulation,
December 9, 2003;
108(23):
2926 - 2933.
[Abstract]
[Full Text]
[PDF]
|
|
|
|
|
|
|
M. J. McGrath, C. A. Mitchell, I. D. Coghill, P. A. Robinson, and S. Brown
Skeletal muscle LIM protein 1 (SLIM1/FHL1) induces {alpha}5{beta}1-integrin-dependent myocyte elongation
Am J Physiol Cell Physiol,
December 1, 2003;
285(6):
C1513 - C1526.
[Abstract]
[Full Text]
[PDF]
|
|
|
|
|
|
|
B. C. Blaxall, R. Spang, H. A. Rockman, and W. J. Koch
Differential myocardial gene expression in the development and rescue of murine heart failure
Physiol Genomics,
October 17, 2003;
15(2):
105 - 114.
[Abstract]
[Full Text]
[PDF]
|
|
|
|
|
|
|
I. D. Coghill, S. Brown, D. L. Cottle, M. J. McGrath, P. A. Robinson, H. H. Nandurkar, J. M. Dyson, and C. A. Mitchell
FHL3 Is an Actin-binding Protein That Regulates {alpha}-Actinin-mediated Actin Bundling: FHL3 LOCALIZES TO ACTIN STRESS FIBERS AND ENHANCES CELL SPREADING AND STRESS FIBER DISASSEMBLY
J. Biol. Chem.,
June 20, 2003;
278(26):
24139 - 24152.
[Abstract]
[Full Text]
[PDF]
|
|
|
|
|
|
|
P. A. Robinson, S. Brown, M. J. McGrath, I. D. Coghill, R. Gurung, and C. A. Mitchell
Skeletal muscle LIM protein 1 regulates integrin-mediated myoblast adhesion, spreading, and migration
Am J Physiol Cell Physiol,
March 1, 2003;
284(3):
C681 - C695.
[Abstract]
[Full Text]
[PDF]
|
|
|
|
|
|
|
M. Steenman, Y.-W. Chen, M. Le Cunff, G. Lamirault, A. Varro, E. Hoffman, and J. J. Leger
Transcriptomal analysis of failing and nonfailing human hearts
Physiol Genomics,
January 15, 2003;
12(2):
97 - 112.
[Abstract]
[Full Text]
[PDF]
|
|
|
|
|
|
|
Y.-W. Chen, G. A Nader, K. R Baar, M. J Fedele, E. P Hoffman, and K. A Esser
Response of rat muscle to acute resistance exercise defined by transcriptional and translational profiling
J. Physiol.,
November 15, 2002;
545(1):
27 - 41.
[Abstract]
[Full Text]
[PDF]
|
|
|
|
|
|
|
J.-J. Hwang, P. D. Allen, G. C. Tseng, C.-W. Lam, L. Fananapazir, V. J. Dzau, and C.-C. Liew
Microarray gene expression profiles in dilated and hypertrophic cardiomyopathic end-stage heart failure
Physiol Genomics,
July 12, 2002;
10(1):
31 - 44.
[Abstract]
[Full Text]
[PDF]
|
|
|
|
