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The FASEB Journal, Vol 5, 3037-3046, Copyright © 1991 by The Federation of American Societies for Experimental Biology

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Regulation of cardiac gene expression during myocardial growth and hypertrophy: molecular studies of an adaptive physiologic response

KR Chien, KU Knowlton, H Zhu and S Chien
Department of Medicine, University of California, San Diego 92093.

Studies from both in vivo and in vitro model systems have provided an initial skeleton of the potential signaling pathways that might regulate cardiac genes during growth and hypertrophy. One of the first detectable changes in cardiac gene expression is the activation of a program of immediate early gene expression, which is distinct for the hypertrophic response, and is conserved in multiple models of both in vivo and in vitro hypertrophy. Diverse and distinct hormonal stimuli have been documented to activate several features of the hypertrophic response, including several autocrine and paracrine factors. Although the signaling mechanisms that link these factors with the activation of cardiac gene expression are unclear, recent studies suggest that the activation of protein kinase C may represent one of the most proximal common events in this signaling cascade. The activation of cardiac target genes induces a program of embryonic gene expression, including the atrial natriuretic factor (ANF) gene. The cis sequences that mediate cardiac-specific and inducible expression of an embryonic marker gene (ANF) can be segregated by studies in both cultured cell models and in vivo models of hypertrophy in transgenic mice, suggesting that specific sets of regulatory elements may exist for inducible expression of this class of cardiac gene responses. However, the induction of a constitutively expressed contractile protein gene (MLC- 2) is mediated by a set of conserved elements that regulate both cardiac-specific and inducible expression. Finally, a subset of cardiac muscle genes appears to be noninducible during in vivo or in vitro hypertrophy in myocardial cells, demonstrating specificity of transcriptional activation during the hypertrophic process. The development of a bona fide in vivo pressure overload model of hypertrophy in a small animal model that can be genetically manipulated, such as the in vivo murine model recently described, should allow a rigorous analysis of the role of these specific signaling mechanisms in the activation of the responses of cardiac genes during the hypertrophic process in vivo.


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S. W. Bahouth, M. J. Beauchamp, and K. N. Vu
Reciprocal Regulation of beta 1-Adrenergic Receptor Gene Transcription by Sp1 and Early Growth Response Gene 1: Induction of EGR-1 Inhibits the Expression of the beta 1-Adrenergic Receptor Gene
Mol. Pharmacol., February 1, 2002; 61(2): 379 - 390.
[Abstract] [Full Text] [PDF]

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 CirculationHome page
D. Hakuno, K. Fukuda, S. Makino, F. Konishi, Y. Tomita, T. Manabe, Y. Suzuki, A. Umezawa, and S. Ogawa
Bone Marrow-Derived Regenerated Cardiomyocytes (CMG Cells) Express Functional Adrenergic and Muscarinic Receptors
Circulation, January 22, 2002; 105(3): 380 - 386.
[Abstract] [Full Text] [PDF]

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 Cold Spring Harb Symp Quant BiolHome page
A. MAASS, J.P. KONHILAS, B.L. STAUFFER, and L.A. LEINWAND
From Sarcomeric Mutations to Heart Disease: Understanding Familial Hypertrophic Cardiomyopathy
Cold Spring Harb Symp Quant Biol, January 1, 2002; 67(0): 409 - 416.
[Abstract] [PDF]

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 HypertensionHome page
T. Omura, M. Yoshiyama, K. Yoshida, Y. Nakamura, S. Kim, H. Iwao, K. Takeuchi, and J. Yoshikawa
Dominant Negative Mutant of c-Jun Inhibits Cardiomyocyte Hypertrophy Induced by Endothelin 1 and Phenylephrine
Hypertension, January 1, 2002; 39(1): 81 - 86.
[Abstract] [Full Text] [PDF]

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 Am. J. Physiol. Cell Physiol.Home page
G.-Q. Xiao, Y. Qu, Z.-Q. Sun, D. Mochly-Rosen, and M. Boutjdir
Evidence for functional role of epsilon PKC isozyme in the regulation of cardiac Na+ channels
Am J Physiol Cell Physiol, November 1, 2001; 281(5): C1477 - C1486.
[Abstract] [Full Text] [PDF]

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 J. Biol. Chem.Home page
D. Le Menuet, R. Isnard, M. Bichara, S. Viengchareun, M. Muffat-Joly, F. Walker, M.-C. Zennaro, and M. Lombes
Alteration of Cardiac and Renal Functions in Transgenic Mice Overexpressing Human Mineralocorticoid Receptor
J. Biol. Chem., October 12, 2001; 276(42): 38911 - 38920.
[Abstract] [Full Text] [PDF]

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 J. Appl. Physiol.Home page
M. A. Perhonen, F. Franco, L. D. Lane, J. C. Buckey, C. G. Blomqvist, J. E. Zerwekh, R. M. Peshock, P. T. Weatherall, and B. D. Levine
Cardiac atrophy after bed rest and spaceflight
J Appl Physiol, August 1, 2001; 91(2): 645 - 653.
[Abstract] [Full Text] [PDF]

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 J Am Coll CardiolHome page
G. Iaccarino, J. R. Keys, A. Rapacciuolo, K. F. Shotwell, R. J. Lefkowitz, H. A. Rockman, and W. J. Koch
Regulation of myocardial {beta}ARK1 expression in catecholamine-induced cardiac hypertrophy in transgenic mice overexpressing {alpha}1B-adrenergic receptors
J. Am. Coll. Cardiol., August 1, 2001; 38(2): 534 - 540.
[Abstract] [Full Text] [PDF]

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 J. Lipid Res.Home page
A. Zahabi and C. F. Deschepper
Long-chain fatty acids modify hypertrophic responses of cultured primary neonatal cardiomyocytes
J. Lipid Res., August 1, 2001; 42(8): 1325 - 1330.
[Abstract] [Full Text] [PDF]

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 Am. J. Pathol.Home page
Y. Okamoto, A. Chaves, J. Chen, R. Kelley, K. Jones, H. G. Weed, K. L. Gardner, L. Gangi, M. Yamaguchi, W. Klomkleaw, et al.
Transgenic Mice with Cardiac-Specific Expression of Activating Transcription Factor 3, a Stress-Inducible Gene, Have Conduction Abnormalities and Contractile Dysfunction
Am. J. Pathol., August 1, 2001; 159(2): 639 - 650.
[Abstract] [Full Text]

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 Mol. Biol. CellHome page
B. Kovacic-Milivojevic, F. Roediger, E. A.C. Almeida, C. H. Damsky, D. G. Gardner, and D. Ilic
Focal Adhesion Kinase and p130Cas Mediate Both Sarcomeric Organization and Activation of Genes Associated with Cardiac Myocyte Hypertrophy
Mol. Biol. Cell, August 1, 2001; 12(8): 2290 - 2307.
[Abstract] [Full Text] [PDF]

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 HypertensionHome page
G. Iaccarino, E. Barbato, E. Cipolleta, A. Esposito, A. Fiorillo, W. J. Koch, and B. Trimarco
Cardiac {beta}ARK1 Upregulation Induced by Chronic Salt Deprivation in Rats
Hypertension, August 1, 2001; 38(2): 255 - 260.
[Abstract] [Full Text] [PDF]

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 Physiol. GenomicsHome page
B. J. ARONOW, T. TOYOKAWA, A. CANNING, K. HAGHIGHI, U. DELLING, E. KRANIAS, J. D. MOLKENTIN, and G. W. DORN II
Divergent transcriptional responses to independent genetic causes of cardiac hypertrophy
Physiol Genomics, June 6, 2001; 6(1): 19 - 28.
[Abstract] [Full Text] [PDF]

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 Eur J Heart FailHome page
S. V. Anisimov, E. G. Lakatta, and K. R. Boheler
Discovering altered genomic expression patterns in heart: transcriptome determination by serial analysis of gene expression
Eur J Heart Fail, June 1, 2001; 3(3): 271 - 281.
[Abstract] [Full Text] [PDF]

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 Am. J. Physiol. Cell Physiol.Home page
C. E. Wright, P. W. Bodell, F. Haddad, A. X. Qin, and K. M. Baldwin
In vivo regulation of the {beta}-myosin heavy chain gene in hypertensive rodent heart
Am J Physiol Cell Physiol, May 1, 2001; 280(5): C1262 - C1276.
[Abstract] [Full Text] [PDF]

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 Mol. Cell. Biol.Home page
K. Kuwahara, Y. Saito, E. Ogawa, N. Takahashi, Y. Nakagawa, Y. Naruse, M. Harada, I. Hamanaka, T. Izumi, Y. Miyamoto, et al.
The Neuron-Restrictive Silencer Element-Neuron-Restrictive Silencer Factor System Regulates Basal and Endothelin 1-Inducible Atrial Natriuretic Peptide Gene Expression in Ventricular Myocytes
Mol. Cell. Biol., March 15, 2001; 21(6): 2085 - 2097.
[Abstract] [Full Text]

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 Mol. Cell. Biol.Home page
B. G. Bruneau, Z.-Z. Bao, D. Fatkin, J. Xavier-Neto, D. Georgakopoulos, C. T. Maguire, C. I. Berul, D. A. Kass, M. L. Kuroski-de Bold, A. J. de Bold, et al.
Cardiomyopathy in Irx4-Deficient Mice Is Preceded by Abnormal Ventricular Gene Expression
Mol. Cell. Biol., March 1, 2001; 21(5): 1730 - 1736.
[Abstract] [Full Text]

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 CirculationHome page
S. Wiese, T. Breyer, A. Dragu, R. Wakili, T. Burkard, S. Schmidt-Schweda, E.-M. Fuchtbauer, U. Dohrmann, F. Beyersdorf, D. Radicke, et al.
Gene Expression of Brain Natriuretic Peptide in Isolated Atrial and Ventricular Human Myocardium : Influence of Angiotensin II and Diastolic Fiber Length
Circulation, December 19, 2000; 102(25): 3074 - 3079.
[Abstract] [Full Text] [PDF]

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 Biol Res NursHome page
S. D. Kim and M. R. Piano
The Natriuretic Peptides: Physiology and Role in Left-Ventricular Dysfunction
Biol Res Nurs, July 1, 2000; 2(1): 15 - 29.
[Abstract] [PDF]

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 Am. J. Physiol. Heart Circ. Physiol.Home page
L. G. Bianciotti and A. J. De Bold
Effect of selective ETA receptor blockade on natriuretic peptide gene expression in DOCA-salt hypertension
Am J Physiol Heart Circ Physiol, July 1, 2000; 279(1): H93 - H101.
[Abstract] [Full Text] [PDF]

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 Am. J. Physiol. Heart Circ. Physiol.Home page
A. E. Stenbit, E. B. Katz, J. C. Chatham, D. L. Geenen, S. M. Factor, R. G. Weiss, T.-S. Tsao, A. Malhotra, V. P. Chacko, C. Ocampo, et al.
Preservation of glucose metabolism in hypertrophic GLUT4-null hearts
Am J Physiol Heart Circ Physiol, July 1, 2000; 279(1): H313 - H318.
[Abstract] [Full Text] [PDF]

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 HypertensionHome page
Y. Aihara, M. Kurabayashi, Y. Saito, Y. Ohyama, T. Tanaka, S.-i. Takeda, K. Tomaru, K.-i. Sekiguchi, M. Arai, T. Nakamura, et al.
Cardiac Ankyrin Repeat Protein Is a Novel Marker of Cardiac Hypertrophy : Role of M-CAT Element Within the Promoter
Hypertension, July 1, 2000; 36(1): 48 - 53.
[Abstract] [Full Text] [PDF]

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 Circ. Res.Home page
D. Mochly-Rosen, G. Wu, H. Hahn, H. Osinska, T. Liron, J. N. Lorenz, A. Yatani, J. Robbins, and G. W. Dorn II
Cardiotrophic Effects of Protein Kinase C {epsilon} : Analysis by In Vivo Modulation of PKC{epsilon} Translocation
Circ. Res., June 9, 2000; 86(11): 1173 - 1179.
[Abstract] [Full Text] [PDF]

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 Am. J. Physiol. Heart Circ. Physiol.Home page
M. R. Morissette, V. P. Sah, C. C. Glembotski, and J. H. Brown
The Rho effector, PKN, regulates ANF gene transcription in cardiomyocytes through a serum response element
Am J Physiol Heart Circ Physiol, June 1, 2000; 278(6): H1769 - H1774.
[Abstract] [Full Text] [PDF]

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 J. Biol. Chem.Home page
S. Chen, J. Cui, K. Nakamura, R. C. J. Ribeiro, B. L. West, and D. G. Gardner
Coactivator-Vitamin D Receptor Interactions Mediate Inhibition of the Atrial Natriuretic Peptide Promoter
J. Biol. Chem., May 12, 2000; 275(20): 15039 - 15048.
[Abstract] [Full Text] [PDF]

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 J. Biol. Chem.Home page
C. Morisco, D. Zebrowski, G. Condorelli, P. Tsichlis, S. F. Vatner, and J. Sadoshima
The Akt-Glycogen Synthase Kinase 3beta Pathway Regulates Transcription of Atrial Natriuretic Factor Induced by beta -Adrenergic Receptor Stimulation in Cardiac Myocytes
J. Biol. Chem., May 5, 2000; 275(19): 14466 - 14475.
[Abstract] [Full Text] [PDF]

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 CirculationHome page
P. D. Sehl, J. T. N. Tai, K. J. Hillan, L. A. Brown, A. Goddard, R. Yang, H. Jin, and D. G. Lowe
Application of cDNA Microarrays in Determining Molecular Phenotype in Cardiac Growth, Development, and Response to Injury
Circulation, April 25, 2000; 101(16): 1990 - 1999.
[Abstract] [Full Text] [PDF]

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 J. Thorac. Cardiovasc. Surg.Home page
A. Meissner, I. Luss, N. Rolf, P. Boknik, U. Kirchhefer, V. Kehm, J. Knapp, B. Linck, H. Luss, F. U. Muller, et al.
THE EARLY RESPONSE GENES C-JUN AND HSP-70 ARE INDUCED IN REGIONAL CARDIAC STUNNING IN CONSCIOUS MAMMALS
J. Thorac. Cardiovasc. Surg., April 1, 2000; 119(4): 820 - 825.
[Abstract] [Full Text] [PDF]

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 Am. J. Physiol. Heart Circ. Physiol.Home page
A. D. Wickenden, R. Kaprielian, X.-M. You, and P. H. Backx
The thyroid hormone analog DITPA restores Ito in rats after myocardial infarction
Am J Physiol Heart Circ Physiol, April 1, 2000; 278(4): H1105 - H1116.
[Abstract] [Full Text] [PDF]

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 FASEB J.Home page
K. A. J. M. VAN DER LEE, P. H. M. WILLEMSEN, G. J. VAN DER VUSSE, and M. VAN BILSEN
Effects of fatty acids on uncoupling protein-2 expression in the rat heart
FASEB J, March 1, 2000; 14(3): 495 - 502.
[Abstract] [Full Text]


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