Endocrinology, Vol 132, 1002-1006, Copyright © 1993 by Endocrine Society

ARTICLES

In vivo regulation of recombinant cardiac myosin heavy chain gene expression by thyroid hormone

K Ojamaa and I Klein
Division of Endocrinology, North Shore University Hospital, Manhasset, New York 11030.

Cardiac myocytes have the unique ability to express exogenous genes that have been injected directly into the heart tissue in vivo. This technique makes it possible to identify cis-acting DNA sequences responsible for the regulation of myocyte-specific genes in a working heart. In these studies we introduced recombinant plasmids containing 5'-flanking sequences of the alpha-myosin heavy chain (alpha MHC) gene into the rat myocardium in order to identify sufficient promoter/enhancer sequences that faithfully reproduced the activity of the endogenous gene. The transcriptional activity of the alpha MHC promoter sequence was measured by the level of activity of the firefly luciferase reporter gene and was reported as the activity relative to a coinjected constitutively active viral promoter construct (pRSVCAT) which corrected for variations in DNA uptake and posttranscriptional events. We report that a recombinant plasmid containing 5'-flanking sequences -2560 to +421 basepairs of the transcriptional start site of the alpha MHC gene was appropriately inactive in the hypothyroid rat heart, in which expression of the endogenous gene was also inhibited. The activity of this promoter sequence was increased 44-fold by thyroid hormone in the hearts of thyroidectomized rats. In contrast, although this recombinant plasmid was appropriately active in the euthyroid myocardium, its activity could not be further stimulated by thyroid hormone. The observation that regulation of the transcriptional activity of the alpha MHC promoter by thyroid hormone was different in euthyroid and hypothyroid hearts suggests that the participation of nuclear regulatory factors, including the thyroid hormone/retinoid family of receptors, may differ according to thyroid status.

This article has been cited by other articles:

				S. Turhan, C. Tulunay, M. Ozduman Cin, A. Gursoy, M. Kilickap, I. Dincer, B. Candemir, S. Gullu, and C. Erol Effects of Thyroxine Therapy on Right Ventricular Systolic and Diastolic Function in Patients with Subclinical Hypothyroidism: A Study by Pulsed Wave Tissue Doppler Imaging J. Clin. Endocrinol. Metab., September 1, 2006; 91(9): 3490 - 3493. [Abstract] [Full Text] [PDF]

				M. Dentice, C. Morisco, M. Vitale, G. Rossi, G. Fenzi, and D. Salvatore The Different Cardiac Expression of the Type 2 Iodothyronine Deiodinase Gene between Human and Rat Is Related to the Differential Response of the dio2 Genes to Nkx-2.5 and GATA-4 Transcription Factors Mol. Endocrinol., August 1, 2003; 17(8): 1508 - 1521. [Abstract] [Full Text] [PDF]

				S. Danzi, K. Ojamaa, and I. Klein Triiodothyronine-mediated myosin heavy chain gene transcription in the heart Am J Physiol Heart Circ Physiol, June 1, 2003; 284(6): H2255 - H2262. [Abstract] [Full Text] [PDF]

				R. Shenoy, I. Klein, and K. Ojamaa Differential regulation of SR calcium transporters by thyroid hormone in rat atria and ventricles Am J Physiol Heart Circ Physiol, October 1, 2001; 281(4): H1690 - H1696. [Abstract] [Full Text] [PDF]

				F. Monzani, V. Di Bello, N. Caraccio, A. Bertini, D. Giorgi, C. Giusti, and E. Ferrannini Effect of Levothyroxine on Cardiac Function and Structure in Subclinical Hypothyroidism: A Double Blind, Placebo-Controlled Study J. Clin. Endocrinol. Metab., March 1, 2001; 86(3): 1110 - 1115. [Abstract] [Full Text]

				I. Klein and K. Ojamaa Editorial: Thyroid Hormone--Targeting the Heart Endocrinology, January 1, 2001; 142(1): 11 - 12. [Full Text] [PDF]

				J. Pachucki, J. Hopkins, R. Peeters, H. Tu, S. D. Carvalho, H. Kaulbach, E. D. Abel, F. E. Wondisford, J. S. Ingwall, and P. R. Larsen Type 2 Iodothyronine Deiodinase Transgene Expression in the Mouse Heart Causes Cardiac-Specific Thyrotoxicosis Endocrinology, January 1, 2001; 142(1): 13 - 20. [Abstract] [Full Text] [PDF]

				K. Ojamaa, A. Kenessey, R. Shenoy, and I. Klein Thyroid hormone metabolism and cardiac gene expression after acute myocardial infarction in the rat Am J Physiol Endocrinol Metab, December 1, 2000; 279(6): E1319 - E1324. [Abstract] [Full Text] [PDF]

				J. Pachucki, L. A. Burmeister, and P. R. Larsen Thyroid Hormone Regulates Hyperpolarization-Activated Cyclic Nucleotide-Gated Channel (HCN2) mRNA in the Rat Heart Circ. Res., September 17, 1999; 85(6): 498 - 503. [Abstract] [Full Text] [PDF]

				K. Ojamaa, A. Sabet, A. Kenessey, R. Shenoy, and I. Klein Regulation of Rat Cardiac Kv1.5 Gene Expression by Thyroid Hormone Is Rapid and Chamber Specific Endocrinology, July 1, 1999; 140(7): 3170 - 3176. [Abstract] [Full Text]

				C. E. Wright, F. Haddad, A. X. Qin, P. W. Bodell, and K. M. Baldwin In vivo regulation of beta -MHC gene in rodent heart: role of T3 and evidence for an upstream enhancer Am J Physiol Cell Physiol, April 1, 1999; 276(4): C883 - C891. [Abstract] [Full Text] [PDF]

				B. Gloss, M. R. Sayen, S. U. Trost, W. F. Bluhm, M. Meyer, E. A. Swanson, S. J. Usala, and W. H. Dillmann Altered Cardiac Phenotype in Transgenic Mice Carrying the {Delta}337 Threonine Thyroid Hormone Receptor {beta} Mutant Derived from the S Family Endocrinology, February 1, 1999; 140(2): 897 - 902. [Abstract] [Full Text]

				K. Hasegawa, S. J. Lee, S. M. Jobe, B. E. Markham, and R. N. Kitsis cis-Acting Sequences That Mediate Induction of ß-Myosin Heavy Chain Gene Expression During Left Ventricular Hypertrophy due to Aortic Constriction Circulation, December 2, 1997; 96(11): 3943 - 3953. [Abstract] [Full Text]

				A. S. Moriscot, M. R. Sayen, R. Hartong, P. Wu, and W. H. Dillmann Transcription of the Rat Sarcoplasmic Reticulum Ca2+ Adenosine Triphosphatase Gene Is Increased by 3,5,3'-Triiodothyronine Receptor Isoform-Specific Interactions with the Myocyte-Specific Enhancer Factor-2a Endocrinology, January 1, 1997; 138(1): 26 - 32. [Abstract] [Full Text] [PDF]

				K. Chang, K Fernandes, and M. Dauncey Molecular characterization of a developmentally regulated porcine skeletal myosin heavy chain gene and its 5' regulatory region J. Cell Sci., January 4, 1995; 108(4): 1779 - 1789. [Abstract] [PDF]