Horm Metab Res 2004; 36(4): 197-202
DOI: 10.1055/s-2004-814445
Original Basic
© Georg Thieme Verlag Stuttgart · New York

Testosterone Regulates mRNA Levels of Calcium Regulatory Proteins in Cardiac Myocytes

K.  L.  Golden1 , J.  D.  Marsh1 , Y.  Jiang1
  • 1Department of Physiology, and Internal Medicine, Wayne State University and John D. Dingell VA Medical Center Detroit, MI, USA
Further Information

Publication History

Received 27 February 2003

Accepted after second Revision 20 November 2003

Publication Date:
28 April 2004 (online)

Abstract

Gender-related differences in cardiac function have been described in the literature, but whether the presence of sex hormones is responsible for these differences remains unclear. This study was designed to determine whether testosterone regulates the gene expression of calcium regulatory proteins in rat heart, thus playing a role in gender-related differences in cardiac performance. Ventricular myocytes were isolated from two-day-old rats and treated with testosterone at varying duration; the levels of gene expression for the androgen receptor (AR) and major calcium regulatory proteins were determined by quantitative real-time PCR. Testosterone (1 µM) treatment induced a maximum increase in β1-adrenergic receptor and L-type calcium channel mRNA levels following an eight hour exposure. Six hours testosterone treatment stimulated a 300-fold increase in androgen receptor message abundance, and Na/Ca exchanger mRNA levels reached a maximum level following twenty-four hour testosterone treatment. Taken together, these data provide the first evidence that testosterone regulates gene expression of the major calcium regulatory proteins in isolated ventricular myocytes, and may thus play a role in the gender-related differences observed in cardiac performance.

References

  • 1 Kimmelstiel C D, Konstam M A. Heart failure in women.  Cardiology. 1995;  86 304-309
  • 2 Vaccarino V, Parsons L, Every N R, Barron H V, Krumholz H M. Sex-based differences in early mortality after myocardial infarction.  N Engl J Med. 1999;  341 217-225
  • 3 Makkar R R, Fromm B S, Steinman R T, Meissner M D, Lehmann M H. Female gender as a risk factor for torsades de pointes associated with cardiovascular drugs.  JAMA. 1993;  270 2590-2597
  • 4 Rautaharju P M, Zhou S H, Wong S, Calhoun H P, Berenson G S, Prineas R, Davignon A. Sex differences in the evolution of the electrocardiographic QT interval with age.  Can J Cardiol. 1992;  8 690-695
  • 5 Rosenkranz-Weiss P, Tomek R J, Mathew J, Eghbali M. Gender-specific differences in expression of mRNAs for functional and structural proteins in rat ventricular myocardium.  J Mol Cell Cardiol. 1994;  26 261-270
  • 6 Scheuer J, Malhotra A, Schaible T F, Capasso J. Effects of gonadectomy and hormonal replacement on rat hearts.  Circ Res. 1987;  61 12-19
  • 7 Marsh J D, Lehmann M H, Ritchie R H, Gwathmey J K, Green G E, Schiebinger R J. Androgen receptors mediate hypertrophy in cardiac myocytes.  Circulation. 1998;  98 256-261
  • 8 Bers D M. Cardiac excitation-contraction coupling.  Nature. 2002;  415 198-205
  • 9 Bassani R A, Bassani J W, Bers D M. Relaxation in ferret ventricular myocytes: unusual interplay among calcium transport systems.  J Physiol. 1994;  476 295-308
  • 10 Bassani J W, Bassani R A, Bers D M. Relaxation in rabbit and rat cardiac cells: species-dependent differences in cellular mechanisms.  J Physiol. 1994;  476 279-293
  • 11 Vizgirda V M, Wahler G M, Sondgeroth K L, Ziolo M T, Schwertz D W. Mechanisms of sex differences in rat cardiac myocyte response to beta-adrenergic stimulation.  Am J Physiol Heart Circ Physiol. 2002;  282 H256-H263
  • 12 Golden K L, Fan Q I, Chen B, Ren J, O’Connor J, Marsh J D. Adrenergic stimulation regulates Na(+)/Ca(2+)Exchanger expression in rat cardiac myocytes.  J Mol Cell Cardiol. 2000;  32 611-620
  • 13 Davidoff A J, Maki T M, Ellingsen O, Marsh J D. Expression of calcium channels in adult cardiac myocytes is regulated by calcium.  J Mol Cell Cardiol. 1997;  29 1791-1803
  • 14 Nakamura T, Sakaeda T, Ohmoto N, Tamura T, Aoyama N, Shirakawa T, Kamigaki T, Nakamura T, Kim K I, Kim S R, Kuroda Y, Matsuo M, Kasuga M, Okumura K. Real-time quantitative polymerase chain reaction for MDR1, MRP1, MRP2, and CYP3A-mRNA levels in Caco-2 cell lines, human duodenal enterocytes, normal colorectal tissues, and colorectal adenocarcinomas.  Drug Metab Dispos. 2002;  30 4-6
  • 15 Wooley P H, Morren R, Andary J, Sud S, Yang S Y, Mayton L, Markel D, Sieving A, Nasser S. Inflammatory responses to orthopaedic biomaterials in the murine air pouch.  Biomaterials. 2002;  23 517-526
  • 16 Ritchie R H, Marsh J D, Lancaster W D, Diglio C A, Schiebinger R J. Bradykinin blocks angiotensin II-induced hypertrophy in the presence of endothelial cells.  Hypertension. 1998;  31 39-44
  • 17 Vermeulen A. Clinical review 24: Androgens in the aging male.  J Clin Endocrinol Metab. 1991;  73 221-224
  • 18 Yan S M, Finato N, di Loreto C, Beltrami C A. Nuclear size of myocardial cells in end-stage cardiomyopathies.  Anal Quant Cytol Histol. 1999;  21 174-180
  • 19 Matturri L, Biondo B, Colombo B, Lavezzi A M, Rossi L. Significance of the DNA synthesis in hypertrophic cardiomyopathies.  Basic Res Cardiol. 1997;  92 85-89
  • 20 Lauer M S, Anderson K M, Larson M G, Levy D. A new method for indexing left ventricular mass for differences in body size.  Am J Cardiol. 1994;  74 487-491
  • 21 Vasan R S, Larson M G, Levy D, Evans J C, Benjamin E J. Distribution and categorization of echocardiographic measurements in relation to reference limits: the Framingham Heart Study: formulation of a height- and sex-specific classification and its prospective validation.  Circulation. 1997;  96 1863-1873
  • 22 Gardin J M, Henry W L, Savage D D, Ware J H, Burn C, Borer J S. Echocardiographic measurements in normal subjects: evaluation of an adult population without clinically apparent heart disease.  J Clin Ultrasound. 1979;  7 439-447
  • 23 Hayward C S, Kalnins W V, Kelly R P. Gender-related differences in left ventricular chamber function.  Cardiovasc Res. 2001;  49 340-350
  • 24 Golden K L, Marsh J D, Jiang Y. Castration reduces mRNA levels for calcium regulatory proteins in rat heart.  Endocrine. 2002;  19 339-344
  • 25 Mora G R, Mahesh V B. Autoregulation of the androgen receptor at the translational level: testosterone induces accumulation of androgen receptor mRNA in the rat ventral prostate polyribosomes.  Steroids. 1999;  64 587-591
  • 26 Wiren K M, Chapman E A, Zhang X W. Osteoblast differentiation influences androgen and estrogen receptor-alpha and -beta expression.  J Endocrinol. 2002;  175 683-694
  • 27 Singh R, Artaza J N, Taylor W E, Gonzalez-Cadavid N F, Bhasin S. Androgens Stimulate Myogenic Differentiation and Inhibit Adipogenesis in C3H 10T1/2 Pluripotent Cells Through an Androgen Receptor-Mediated Pathway.  Endocrinology. 2003;  144 5081-5088
  • 28 Ubels J L, Wertz J T, Ingersoll K E, Jackson R S, Aupperlee M D. Down-regulation of androgen receptor expression and inhibition of lacrimal gland cell proliferation by retinoic acid.  Exp Eye Res. 2002;  75 561-571
  • 29 Muller J G, Isomatsu Y, Koushik S V, O’Quinn M, Xu L, Kappler C S, Hapke E, Zile M R, Conway S J, Menick D R. Cardiac-specific expression and hypertrophic upregulation of the feline Na(+)-Ca(2+) exchanger gene H1-promoter in a transgenic mouse model.  Circ Res. 2002;  90 158-164
  • 30 Pogwizd S M, Schlotthauer K, Li L, Yuan W, Bers D M. Arrhythmogenesis and contractile dysfunction in heart failure: Roles of sodium-calcium exchange, inward rectifier potassium current, and residual beta-adrenergic responsiveness.  Circ Res. 2001;  88 1159-1167
  • 31 Pogwizd S M. Increased Na(+)-Ca(2+) exchanger in the failing heart.  Circ Res. 2000;  87 641-643
  • 32 Hintz K K, Wold L E, Colligan P B, Scott G I, Lee K J, Sowers J R, Ren J. Influence of ovariectomy on ventricular myocyte contraction in simulated diabetes.  J Biomed Sci. 2001;  8 307-313
  • 33 Koenig H, Fan C C, Goldstone A D, Lu C Y, Trout J J. Polyamines mediate androgenic stimulation of calcium fluxes and membrane transport in rat heart myocytes.  Circ Res. 1989;  64 415-426
  • 34 Gomez A M, Valdivia H H, Cheng H, Lederer M R, Santana L F, Cannell M B, McCune S A, Altschuld R A, Lederer W J. Defective excitation-contraction coupling in experimental cardiac hypertrophy and heart failure.  Science. 1997;  276 800-806
  • 35 Scamps F, Mayoux E, Charlemagne D, Vassort G. Calcium current in single cells isolated from normal and hypertrophied rat heart. Effects of beta-adrenergic stimulation.  Circ Res. 1990;  67 199-208
  • 36 Richard S, Leclercq F, Lemaire S, Piot C, Nargeot J. Ca2+ currents in compensated hypertrophy and heart failure.  Cardiovasc Res. 1998;  37 300-311
  • 37 Keung E C. Calcium current is increased in isolated adult myocytes from hypertrophied rat myocardium.  Circ Res. 1989;  64 753-763
  • 38 Liu L, Fan Q I, El Zaru M R, Vanderpool K, Hines R N, Marsh J D. Regulation of DHP receptor expression by elements in the 5'-flanking sequence.  Am J Physiol Heart Circ Physiol. 2000;  278 H1153-H1162
  • 39 Engelhardt S, Boknik P, Keller U, Neumann J, Lohse M J, Hein L. Early impairment of calcium handling and altered expression of junction in hearts of mice overexpressing the beta1-adrenergic receptor.  FASEB J. 2001;  15 2718-2720
  • 40 Evanko D S, Ellis C E, Venkatachalam V, Frielle T. Preliminary analysis of the transcriptional regulation of the human beta 1-adrenergic receptor gene.  Biochem Biophys Res Commun. 1998;  244 395-402
  • 41 Tseng Y T, Stabila J P, Nguyen T T, McGonnigal B G, Waschek J A, Padbury J F. A novel glucocorticoid regulatory unit mediates the hormone responsiveness of the beta1-adrenergic receptor gene.  Mol Cell Endocrinol. 2001;  181 165-178
  • 42 Jorgensen J S, Nilson J H. AR suppresses transcription of the alpha glycoprotein hormone subunit gene through protein-protein interactions with cJun and activation transcription factor 2.  Mol Endocrinol. 2001;  15 1496-1504
  • 43 Golden K L, Ren J, O’Connor J, Dean A, DiCarlo S E, Marsh J D. In vivo regulation of Na/Ca exchanger expression by adrenergic effectors.  Am J Physiol Heart Circ Physiol. 2001;  280 H1376-H1382
  • 44 Golden K L, Ren J, Dean A, Marsh J D. Norepinephrine regulates the in vivo expression of the L-type calcium channel.  Mol Cell Biochem. 2002;  236 107-114
  • 45 Golden K L, Marsh J D, Jiang Y, Brown T, Moulden J. Gonadectomy of adult male rats reduces contractility of isolated cardiac myocytes.  Am J Physiol Endocrinol Metab. 2003;  285 E449-E453
  • 46 Maki T, Gruver E J, Davidoff A J, Izzo N, Toupin D, Colucci W, Marks A R, Marsh J D. Regulation of calcium channel expression in neonatal myocytes by catecholamines.  J Clin Invest. 1996;  97 656-663
  • 47 Wallukat G. The beta-adrenergic receptors.  Herz. 2002;  27 683-690

K. L. Golden, Ph. D.

Wayne State University School of Medicine

421 E. Canfield Ave. · Detroit · MI 48201

Phone: +1(313)576-4480

Fax: +1(313)577-1112

Email: kgolden@med.wayne.edu

    >