Skip to main content
PMC home page
The Journal of Clinical Investigation logoLink to The Journal of Clinical Investigation
. 1997 Oct 1;100(7):1742–1749. doi: 10.1172/JCI119699

Thyroid hormone improves function and Ca2+ handling in pressure overload hypertrophy. Association with increased sarcoplasmic reticulum Ca2+-ATPase and alpha-myosin heavy chain in rat hearts.

K C Chang 1, V M Figueredo 1, J H Schreur 1, K Kariya 1, M W Weiner 1, P C Simpson 1, S A Camacho 1
PMCID: PMC508357  PMID: 9312172

Abstract

We asked whether thyroid hormone (T4) would improve heart function in left ventricular hypertrophy (LVH) induced by pressure overload (aortic banding). After banding for 10-22 wk, rats were treated with T4 or saline for 10-14 d. Isovolumic LV pressure and cytosolic [Ca2+] (indo-1) were assessed in perfused hearts. Sarcoplasmic reticulum Ca2+-ATPase (SERCA), phospholamban, and alpha- and beta-myosin heavy chain (MHC) proteins were assayed in homogenates of myocytes isolated from the same hearts. Of 14 banded hearts treated with saline, 8 had compensated LVH with normal function (LVHcomp), whereas 6 had abnormal contraction, relaxation, and calcium handling (LVHdecomp). In contrast, banded animals treated with T4 had no myocardial dysfunction; these hearts had increased contractility, and faster relaxation and cytosolic [Ca2+] decline compared with LVHcomp and LVHdecomp. Myocytes from banded hearts treated with T4 were hypertrophied but had increased concentrations of alpha-MHC and SERCA proteins, similar to physiological hypertrophy induced by exercise. Thus thyroid hormone improves LV function and calcium handling in pressure overload hypertrophy, and these beneficial effects are related to changes in myocyte gene expression. Induction of physiological hypertrophy by thyroid hormone-like signaling might be a therapeutic strategy for treating cardiac dysfunction in pathological hypertrophy and heart failure.

Full Text

The Full Text of this article is available as a PDF (280.1 KB).

Selected References

These references are in PubMed. This may not be the complete list of references from this article.

  1. Arai M., Matsui H., Periasamy M. Sarcoplasmic reticulum gene expression in cardiac hypertrophy and heart failure. Circ Res. 1994 Apr;74(4):555–564. doi: 10.1161/01.res.74.4.555. [DOI] [PubMed] [Google Scholar]
  2. Bing O. H., Brooks W. W., Conrad C. H., Sen S., Perreault C. L., Morgan J. P. Intracellular calcium transients in myocardium from spontaneously hypertensive rats during the transition to heart failure. Circ Res. 1991 May;68(5):1390–1400. doi: 10.1161/01.res.68.5.1390. [DOI] [PubMed] [Google Scholar]
  3. Bing O. H., Hague N. L., Perreault C. L., Conrad C. H., Brooks W. W., Sen S., Morgan J. P. Thyroid hormone effects on intracellular calcium and inotropic responses of rat ventricular myocardium. Am J Physiol. 1994 Sep;267(3 Pt 2):H1112–H1121. doi: 10.1152/ajpheart.1994.267.3.H1112. [DOI] [PubMed] [Google Scholar]
  4. Brandes R., Figueredo V. M., Camacho S. A., Baker A. J., Weiner M. W. Investigation of factors affecting fluorometric quantitation of cytosolic [Ca2+] in perfused hearts. Biophys J. 1993 Nov;65(5):1983–1993. doi: 10.1016/S0006-3495(93)81275-X. [DOI] [PMC free article] [PubMed] [Google Scholar]
  5. Brandes R., Figueredo V. M., Camacho S. A., Baker A. J., Weiner M. W. Quantitation of cytosolic [Ca2+] in whole perfused rat hearts using Indo-1 fluorometry. Biophys J. 1993 Nov;65(5):1973–1982. doi: 10.1016/S0006-3495(93)81274-8. [DOI] [PMC free article] [PubMed] [Google Scholar]
  6. Brandes R., Figueredo V. M., Camacho S. A., Massie B. M., Weiner M. W. Suppression of motion artifacts in fluorescence spectroscopy of perfused hearts. Am J Physiol. 1992 Sep;263(3 Pt 2):H972–H980. doi: 10.1152/ajpheart.1992.263.3.H972. [DOI] [PubMed] [Google Scholar]
  7. Buttrick P. M., Malhotra A., Scheuer J. Effects of systolic overload and swim training on cardiac mechanics and biochemistry in rats. J Appl Physiol (1985) 1988 Apr;64(4):1466–1471. doi: 10.1152/jappl.1988.64.4.1466. [DOI] [PubMed] [Google Scholar]
  8. Camacho S. A., Brandes R., Figueredo V. M., Weiner M. W. Ca2+ transient decline and myocardial relaxation are slowed during low flow ischemia in rat hearts. J Clin Invest. 1994 Mar;93(3):951–957. doi: 10.1172/JCI117101. [DOI] [PMC free article] [PubMed] [Google Scholar]
  9. Cannon R. O., 3rd, Schenke W. H., Leon M. B., Rosing D. R., Urqhart J., Epstein S. E. Limited coronary flow reserve after dipyridamole in patients with ergonovine-induced coronary vasoconstriction. Circulation. 1987 Jan;75(1):163–174. doi: 10.1161/01.cir.75.1.163. [DOI] [PubMed] [Google Scholar]
  10. Chang K. C., Schreur J. H., Weiner M. W., Camacho S. A. Impaired Ca2+ handling is an early manifestation of pressure-overload hypertrophy in rat hearts. Am J Physiol. 1996 Jul;271(1 Pt 2):H228–H234. doi: 10.1152/ajpheart.1996.271.1.H228. [DOI] [PubMed] [Google Scholar]
  11. Cohn J. N., Bristow M. R., Chien K. R., Colucci W. S., Frazier O. H., Leinwand L. A., Lorell B. H., Moss A. J., Sonnenblick E. H., Walsh R. A. Report of the National Heart, Lung, and Blood Institute Special Emphasis Panel on Heart Failure Research. Circulation. 1997 Feb 18;95(4):766–770. doi: 10.1161/01.cir.95.4.766. [DOI] [PubMed] [Google Scholar]
  12. Duerr R. L., Huang S., Miraliakbar H. R., Clark R., Chien K. R., Ross J., Jr Insulin-like growth factor-1 enhances ventricular hypertrophy and function during the onset of experimental cardiac failure. J Clin Invest. 1995 Feb;95(2):619–627. doi: 10.1172/JCI117706. [DOI] [PMC free article] [PubMed] [Google Scholar]
  13. Esser K. A., Boluyt M. O., White T. P. Separation of cardiac myosin heavy chains by gradient SDS-PAGE. Am J Physiol. 1988 Sep;255(3 Pt 2):H659–H663. doi: 10.1152/ajpheart.1988.255.3.H659. [DOI] [PubMed] [Google Scholar]
  14. Fazio S., Sabatini D., Capaldo B., Vigorito C., Giordano A., Guida R., Pardo F., Biondi B., Saccà L. A preliminary study of growth hormone in the treatment of dilated cardiomyopathy. N Engl J Med. 1996 Mar 28;334(13):809–814. doi: 10.1056/NEJM199603283341301. [DOI] [PubMed] [Google Scholar]
  15. Feldman A. M., Weinberg E. O., Ray P. E., Lorell B. H. Selective changes in cardiac gene expression during compensated hypertrophy and the transition to cardiac decompensation in rats with chronic aortic banding. Circ Res. 1993 Jul;73(1):184–192. doi: 10.1161/01.res.73.1.184. [DOI] [PubMed] [Google Scholar]
  16. Figueredo V. M., Brandes R., Weiner M. W., Massie B. M., Camacho S. A. Cardiac contractile dysfunction during mild coronary flow reductions is due to an altered calcium-pressure relationship in rat hearts. J Clin Invest. 1992 Nov;90(5):1794–1802. doi: 10.1172/JCI116054. [DOI] [PMC free article] [PubMed] [Google Scholar]
  17. Figueredo V. M., Brandes R., Weiner M. W., Massie B. M., Camacho S. A. Endocardial versus epicardial differences of intracellular free calcium under normal and ischemic conditions in perfused rat hearts. Circ Res. 1993 May;72(5):1082–1090. doi: 10.1161/01.res.72.5.1082. [DOI] [PubMed] [Google Scholar]
  18. Gay R. G., Graham S., Aguirre M., Goldman S., Morkin E. Effects of 10- to 12-day treatment with L-thyroxine in rats with myocardial infarction. Am J Physiol. 1988 Oct;255(4 Pt 2):H801–H806. doi: 10.1152/ajpheart.1988.255.4.H801. [DOI] [PubMed] [Google Scholar]
  19. Gay R., Gustafson T. A., Goldman S., Morkin E. Effects of L-thyroxine in rats with chronic heart failure after myocardial infarction. Am J Physiol. 1987 Aug;253(2 Pt 2):H341–H346. doi: 10.1152/ajpheart.1987.253.2.H341. [DOI] [PubMed] [Google Scholar]
  20. Gerdes A. M., Moore J. A., Hines J. M., Kirkland P. A., Bishop S. P. Regional differences in myocyte size in normal rat heart. Anat Rec. 1986 Aug;215(4):420–426. doi: 10.1002/ar.1092150414. [DOI] [PubMed] [Google Scholar]
  21. Isenberg G., Klockner U. Calcium tolerant ventricular myocytes prepared by preincubation in a "KB medium". Pflugers Arch. 1982 Oct;395(1):6–18. doi: 10.1007/BF00584963. [DOI] [PubMed] [Google Scholar]
  22. Izumo S., Lompré A. M., Matsuoka R., Koren G., Schwartz K., Nadal-Ginard B., Mahdavi V. Myosin heavy chain messenger RNA and protein isoform transitions during cardiac hypertrophy. Interaction between hemodynamic and thyroid hormone-induced signals. J Clin Invest. 1987 Mar;79(3):970–977. doi: 10.1172/JCI112908. [DOI] [PMC free article] [PubMed] [Google Scholar]
  23. Kiss E., Ball N. A., Kranias E. G., Walsh R. A. Differential changes in cardiac phospholamban and sarcoplasmic reticular Ca(2+)-ATPase protein levels. Effects on Ca2+ transport and mechanics in compensated pressure-overload hypertrophy and congestive heart failure. Circ Res. 1995 Oct;77(4):759–764. doi: 10.1161/01.res.77.4.759. [DOI] [PubMed] [Google Scholar]
  24. Kiss E., Jakab G., Kranias E. G., Edes I. Thyroid hormone-induced alterations in phospholamban protein expression. Regulatory effects on sarcoplasmic reticulum Ca2+ transport and myocardial relaxation. Circ Res. 1994 Aug;75(2):245–251. doi: 10.1161/01.res.75.2.245. [DOI] [PubMed] [Google Scholar]
  25. Klemperer J. D., Ojamaa K., Klein I. Thyroid hormone therapy in cardiovascular disease. Prog Cardiovasc Dis. 1996 Jan-Feb;38(4):329–336. doi: 10.1016/s0033-0620(96)80017-x. [DOI] [PubMed] [Google Scholar]
  26. Koide M., Nagatsu M., Zile M. R., Hamawaki M., Swindle M. M., Keech G., DeFreyte G., Tagawa H., Cooper G., 4th, Carabello B. A. Premorbid determinants of left ventricular dysfunction in a novel model of gradually induced pressure overload in the adult canine. Circulation. 1997 Mar 18;95(6):1601–1610. doi: 10.1161/01.cir.95.6.1601. [DOI] [PubMed] [Google Scholar]
  27. Loh E., Swain J. L. Growth hormone for heart failure--cause for cautious optimism. N Engl J Med. 1996 Mar 28;334(13):856–857. doi: 10.1056/NEJM199603283341309. [DOI] [PubMed] [Google Scholar]
  28. Lorell B. H. Significance of diastolic dysfunction of the heart. Annu Rev Med. 1991;42:411–436. doi: 10.1146/annurev.me.42.020191.002211. [DOI] [PubMed] [Google Scholar]
  29. Lytton J., Westlin M., Burk S. E., Shull G. E., MacLennan D. H. Functional comparisons between isoforms of the sarcoplasmic or endoplasmic reticulum family of calcium pumps. J Biol Chem. 1992 Jul 15;267(20):14483–14489. [PubMed] [Google Scholar]
  30. MacKinnon R., Gwathmey J. K., Allen P. D., Briggs G. M., Morgan J. P. Modulation by the thyroid state of intracellular calcium and contractility in ferret ventricular muscle. Circ Res. 1988 Dec;63(6):1080–1089. doi: 10.1161/01.res.63.6.1080. [DOI] [PubMed] [Google Scholar]
  31. Mahaffey K. W., Raya T. E., Pennock G. D., Morkin E., Goldman S. Left ventricular performance and remodeling in rabbits after myocardial infarction. Effects of a thyroid hormone analogue. Circulation. 1995 Feb 1;91(3):794–801. doi: 10.1161/01.cir.91.3.794. [DOI] [PubMed] [Google Scholar]
  32. Malhotra A., Penpargkul S., Schaible T., Scheuer J. Contractile proteins and sarcoplasmic reticulum in physiologic cardiac hypertrophy. Am J Physiol. 1981 Aug;241(2):H263–H267. doi: 10.1152/ajpheart.1981.241.2.H263. [DOI] [PubMed] [Google Scholar]
  33. Morris G. L., Cheng H. C., Colyer J., Wang J. H. Phospholamban regulation of cardiac sarcoplasmic reticulum (Ca(2+)-Mg2+)-ATPase. Mechanism of regulation and site of monoclonal antibody interaction. J Biol Chem. 1991 Jun 15;266(17):11270–11275. [PubMed] [Google Scholar]
  34. Ojamaa K., Klein I. Thyroid hormone regulation of alpha-myosin heavy chain promoter activity assessed by in vivo DNA transfer in rat heart. Biochem Biophys Res Commun. 1991 Sep 30;179(3):1269–1275. doi: 10.1016/0006-291x(91)91710-t. [DOI] [PubMed] [Google Scholar]
  35. Ojamaa K., Klemperer J. D., MacGilvray S. S., Klein I., Samarel A. Thyroid hormone and hemodynamic regulation of beta-myosin heavy chain promoter in the heart. Endocrinology. 1996 Mar;137(3):802–808. doi: 10.1210/endo.137.3.8603588. [DOI] [PubMed] [Google Scholar]
  36. Ojamaa K., Samarel A. M., Kupfer J. M., Hong C., Klein I. Thyroid hormone effects on cardiac gene expression independent of cardiac growth and protein synthesis. Am J Physiol. 1992 Sep;263(3 Pt 1):E534–E540. doi: 10.1152/ajpendo.1992.263.3.E534. [DOI] [PubMed] [Google Scholar]
  37. Pennock G. D., Raya T. E., Bahl J. J., Goldman S., Morkin E. Combination treatment with captopril and the thyroid hormone analogue 3,5-diiodothyropropionic acid. A new approach to improving left ventricular performance in heart failure. Circulation. 1993 Sep;88(3):1289–1298. doi: 10.1161/01.cir.88.3.1289. [DOI] [PubMed] [Google Scholar]
  38. Rohrer D. K., Hartong R., Dillmann W. H. Influence of thyroid hormone and retinoic acid on slow sarcoplasmic reticulum Ca2+ ATPase and myosin heavy chain alpha gene expression in cardiac myocytes. Delineation of cis-active DNA elements that confer responsiveness to thyroid hormone but not to retinoic acid. J Biol Chem. 1991 May 5;266(13):8638–8646. [PubMed] [Google Scholar]
  39. Rohrer D., Dillmann W. H. Thyroid hormone markedly increases the mRNA coding for sarcoplasmic reticulum Ca2+-ATPase in the rat heart. J Biol Chem. 1988 May 25;263(15):6941–6944. [PubMed] [Google Scholar]
  40. Ross J., Jr On variations in the cardiac hypertrophic response to pressure overload. Circulation. 1997 Mar 18;95(6):1349–1351. doi: 10.1161/01.cir.95.6.1349. [DOI] [PubMed] [Google Scholar]
  41. Schaible T. F., Ciambrone G. J., Capasso J. M., Scheuer J. Cardiac conditioning ameliorates cardiac dysfunction associated with renal hypertension in rats. J Clin Invest. 1984 Apr;73(4):1086–1094. doi: 10.1172/JCI111294. [DOI] [PMC free article] [PubMed] [Google Scholar]
  42. Schaible T. F., Malhotra A., Ciambrone G. J., Scheuer J. Chronic swimming reverses cardiac dysfunction and myosin abnormalities in hypertensive rats. J Appl Physiol (1985) 1986 Apr;60(4):1435–1441. doi: 10.1152/jappl.1986.60.4.1435. [DOI] [PubMed] [Google Scholar]
  43. Schaible T. F., Scheuer J. Cardiac adaptations to chronic exercise. Prog Cardiovasc Dis. 1985 Mar-Apr;27(5):297–324. doi: 10.1016/s0033-0620(85)80001-3. [DOI] [PubMed] [Google Scholar]
  44. Schreur J. H., Figueredo V. M., Miyamae M., Shames D. M., Baker A. J., Camacho S. A. Cytosolic and mitochondrial [Ca2+] in whole hearts using indo-1 acetoxymethyl ester: effects of high extracellular Ca2+. Biophys J. 1996 Jun;70(6):2571–2580. doi: 10.1016/S0006-3495(96)79828-4. [DOI] [PMC free article] [PubMed] [Google Scholar]
  45. VanBuren P., Harris D. E., Alpert N. R., Warshaw D. M. Cardiac V1 and V3 myosins differ in their hydrolytic and mechanical activities in vitro. Circ Res. 1995 Aug;77(2):439–444. doi: 10.1161/01.res.77.2.439. [DOI] [PubMed] [Google Scholar]
  46. Wier W. G. Cytoplasmic [Ca2+] in mammalian ventricle: dynamic control by cellular processes. Annu Rev Physiol. 1990;52:467–485. doi: 10.1146/annurev.ph.52.030190.002343. [DOI] [PubMed] [Google Scholar]
  47. Yang R., Bunting S., Gillett N., Clark R., Jin H. Growth hormone improves cardiac performance in experimental heart failure. Circulation. 1995 Jul 15;92(2):262–267. doi: 10.1161/01.cir.92.2.262. [DOI] [PubMed] [Google Scholar]
  48. Yao J., Eghbali M. Decreased collagen gene expression and absence of fibrosis in thyroid hormone-induced myocardial hypertrophy. Response of cardiac fibroblasts to thyroid hormone in vitro. Circ Res. 1992 Oct;71(4):831–839. doi: 10.1161/01.res.71.4.831. [DOI] [PubMed] [Google Scholar]
  49. de la Bastie D., Levitsky D., Rappaport L., Mercadier J. J., Marotte F., Wisnewsky C., Brovkovich V., Schwartz K., Lompré A. M. Function of the sarcoplasmic reticulum and expression of its Ca2(+)-ATPase gene in pressure overload-induced cardiac hypertrophy in the rat. Circ Res. 1990 Feb;66(2):554–564. doi: 10.1161/01.res.66.2.554. [DOI] [PubMed] [Google Scholar]

Articles from Journal of Clinical Investigation are provided here courtesy of American Society for Clinical Investigation

RESOURCES