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Non-genomic effects of thyroid hormone in adult cardiac myocytes: relevance to gene expression and cell growth

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Abstract

Besides the well-characterized genomic action of thyroid hormone (TH), mediated by thyroid hormone receptors (TRs), accumulating data support the so-called non-genomic action of TH, which is often related to activation of signalling pathways. In this study, we sought to determine whether TH activates intracellular signalling pathways in the adult cardiac myocytes and whether such activation modulates cell growth and the expression of target proteins important in cardiac function. We demonstrate that TH promotes a rapid increase in the phosphorylation of several kinases, ERK1/2, PKCδ, p38-MAPK and Akt. This activation is inhibited by triiodothyroacetic acid (triac), which is a TH analogue known to displace the hormone from membrane bound receptors, indicating that this TH effect is mediated through a cell membrane-initiated mechanism. Furthermore, using specific inhibitors of the TH-activated kinases, we show that the long-term effects of TH on the expression of sarcoplasmic reticulum Ca2+-ATPase (SERCA), α- and β-myosin heavy chain (MHC) and cell growth are reverted, implying that what is initiated as a non-genomic action of the hormone interfaces with genomic effects. These data provide further insights into the underlying mechanisms of TH action in the heart with potentially important implications in the management of cardiac pathology.

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References

  1. Kahaly GJ, Dillmann WH (2005) Thyroid hormone action in the heart. Endocr Rev 26:704–728

    Article  CAS  PubMed  Google Scholar 

  2. Pantos C, Mourouzis I, Cokkinos DV (2010) Rebuilding the post-infarcted myocardium by activating ‘physiologic’ hypertrophic signalling pathways: the thyroid hormone paradigm. Heart Fail Rev 15(2):143–154

    Article  CAS  PubMed  Google Scholar 

  3. Pantos C, Mourouzis I, Xinaris C, Cokkinos DV (2008) Thyroid hormone and myocardial ischaemia. J Steroid Biochem Mol Biol 109:314–322

    Article  CAS  PubMed  Google Scholar 

  4. Zhang J, Lazar MA (2000) The mechanism of action of thyroid hormones. Annu Rev Physiol 62:439–466

    Article  CAS  PubMed  Google Scholar 

  5. Klein I, Ojamaa K (2001) Thyroid hormone and the cardiovascular system. N Engl J Med 344:501–509

    Article  CAS  PubMed  Google Scholar 

  6. Davis PJ, Leonard J, Davis FB (2008) Mechanisms of nongenomic actions of thyroid hormone. Front Neuroendocrinol 29:211–218

    CAS  PubMed  Google Scholar 

  7. Lin HY, Davis FB, Gordinier JK, Martino LJ, Davis PJ (1999) Thyroid hormone induces activation of mitogen-activated protein kinase in cultured cells. Am J Physiol 276:C1014–C1024

    CAS  PubMed  Google Scholar 

  8. Alisi A, Spagnuolo S, Napoletano S, Spaziani A, Leoni S (2004) Thyroid hormones regulate DNA-synthesis and cell-cycle proteins by activation of PKCalpha and p42/44 MAPK in chick embryo hepatocytes. J Cell Physiol 201:259–265

    Article  CAS  PubMed  Google Scholar 

  9. Cao X, Kambe F, Moeller LC, Refetoff S, Seo H (2005) Thyroid hormone induces rapid activation of Akt/protein kinase B-mammalian target of rapamycin-p70S6K cascade through phosphatidylinositol 3-kinase in human fibroblasts. Mol Endocrinol 19:102–112

    Article  CAS  PubMed  Google Scholar 

  10. Kinugawa K, Jeong MY, Bristow MR, Long CS (2005) Thyroid hormone induces cardiac myocyte hypertrophy in a thyroid hormone receptor alpha1-specific manner that requires TAK1 and p38 mitogen-activated protein kinase. Mol Endocrinol 19:1618–1628

    Article  CAS  PubMed  Google Scholar 

  11. Kenessey A, Ojamaa K (2006) Thyroid hormone stimulates protein synthesis in the cardiomyocyte by activating the Akt-mTOR and p70S6K pathways. J Biol Chem 281:20666–20672

    Article  CAS  PubMed  Google Scholar 

  12. Bergh JJ, Lin HY, Lansing L, Mohamed SN, Davis FB, Mousa S, Davis PJ (2005) Integrin alphaVbeta3 contains a cell surface receptor site for thyroid hormone that is linked to activation of mitogen-activated protein kinase and induction of angiogenesis. Endocrinology 146:2864–2871

    Article  CAS  PubMed  Google Scholar 

  13. Incerpi S, De Vito P, Luly P, Spagnuolo S, Leoni S (2002) Short-term effects of thyroid hormones and 3,5-diiodothyronine on membrane transport systems in chick embryo hepatocytes. Endocrinology 143:1660–1668

    Article  CAS  PubMed  Google Scholar 

  14. D’Arezzo S, Incerpi S, Davis FB, Acconcia F, Marino M, Farias RN, Davis PJ (2004) Rapid nongenomic effects of 3,5,3′-triiodo-l-thyronine on the intracellular pH of L-6 myoblasts are mediated by intracellular calcium mobilization and kinase pathways. Endocrinology 145:5694–5703

    Article  PubMed  Google Scholar 

  15. Davis PJ, Davis FB, Lin HY (2008) Promotion by thyroid hormone of cytoplasm-to-nucleus shuttling of thyroid hormone receptors. Steroids 73:1013–1017

    Article  CAS  PubMed  Google Scholar 

  16. Lin HY, Shih A, Davis FB, Davis PJ (1999) Thyroid hormone promotes the phosphorylation of STAT3 and potentiates the action of epidermal growth factor in cultured cells. Biochem J 338:427–432

    Article  CAS  PubMed  Google Scholar 

  17. Shih A, Lin HY, Davis FB, Davis PJ (2001) Thyroid hormone promotes serine phosphorylation of p53 by mitogen-activated protein kinase. Biochemistry 40:2870–2878

    Article  CAS  PubMed  Google Scholar 

  18. Pantos C, Xinaris C, Mourouzis I, Malliopoulou V, Kardami E, Cokkinos DV (2007) Thyroid hormone changes cardiomyocyte shape and geometry via ERK signalling pathway: potential therapeutic implications in reversing cardiac remodeling? Mol Cell Biochem 297:65–72

    Article  CAS  PubMed  Google Scholar 

  19. Clerk A, Cullingford TE, Fuller SJ, Giraldo A, Markou T, Pikkarainen S, Sugden PH (2007) Signalling pathways mediating cardiac myocyte gene expression in physiological and stress responses. J Cell Physiol 212:311–322

    Article  CAS  PubMed  Google Scholar 

  20. Dillmann W (2010) Cardiac hypertrophy and thyroid hormone signalling. Heart Fail Rev 15(2):125–132

    Article  CAS  PubMed  Google Scholar 

  21. Markou T, Cieslak D, Gaitanaki C, Lazou A (2009) Differential roles of MAPKs and MSK1 signalling pathways in the regulation of c-Jun during phenylephrine-induced cardiac myocyte hypertrophy. Mol Cell Biochem 322:103–112

    Article  CAS  PubMed  Google Scholar 

  22. Ishisaki A, Tokuda H, Yoshida M, Hirade K, Kunieda K, Hatakeyama D, Shibata T, Kozawa O (2004) Activation of p38 mitogen-activated protein kinase mediates thyroid hormone-stimulated osteocalcin synthesis in osteoblasts. Mol Cell Endocrinol 214:189–195

    Article  CAS  PubMed  Google Scholar 

  23. Davis PJ, Davis FB, Blas SD (1982) Studies on the mechanism of thyroid hormone stimulation in vitro of human red cell Ca2+-ATPase activity. Life Sci 30:675–682

    Article  CAS  PubMed  Google Scholar 

  24. Davis PJ, Shih A, Lin HY, Martino LJ, Davis FB (2000) Thyroxine promotes association of mitogen-activated protein kinase and nuclear thyroid hormone receptor (TR) and causes serine phosphorylation of TR. J Biol Chem 275:38032–38039

    Article  CAS  PubMed  Google Scholar 

  25. Rohrer DK, Hartong R, Dillmann WH (1991) 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 266:8638–8646

    CAS  PubMed  Google Scholar 

  26. Kimura Y, Otsu K, Nishida K, Kuzuya T, Tada M (1994) Thyroid hormone enhances Ca2+ pumping activity of the cardiac sarcoplasmic reticulum by increasing Ca2+ ATPase and decreasing phospholamban expression. J Mol Cell Cardiol 26:1145–1154

    Article  CAS  PubMed  Google Scholar 

  27. Moriyama K, Tagami T, Akamizu T, Usui T, Saijo M, Kanamoto N, Hataya Y, Shimatsu A, Kuzuya H, Nakao K (2002) Thyroid hormone action is disrupted by bisphenol A as an antagonist. J Clin Endocrinol Metab 87:5185–5190

    Article  CAS  PubMed  Google Scholar 

  28. Davis FB, Mousa SA, O’Connor L, Mohamed S, Lin HY, Cao HJ, Davis PJ (2004) Proangiogenic action of thyroid hormone is fibroblast growth factor-dependent and is initiated at the cell surface. Circ Res 94:1500–1506

    Article  CAS  PubMed  Google Scholar 

  29. Diniz GP, Carneiro-Ramos MS, Barreto-Chaves ML (2009) Angiotensin type 1 receptor mediates thyroid hormone-induced cardiomyocyte hypertrophy through the Akt/GSK-3beta/mTOR signalling pathway. Basic Res Cardiol 104:653–667

    Article  CAS  PubMed  Google Scholar 

  30. Wu XD, Dai DZ, Zhang QP, Gao F (2004) Propranolol and verapamil inhibit mRNA expression of RyR2 and SERCA in l-thyroxin-induced rat ventricular hypertrophy. Acta Pharmacol Sin 25:347–351

    CAS  PubMed  Google Scholar 

  31. Davis PJ, Davis FB, Lin HY, Mousa SA, Zhou M, Luidens MK (2009) Translational implications of nongenomic actions of thyroid hormone initiated at its integrin receptor. Am J Physiol Endocrinol Metab 297(6):E1238–E1246

    Article  CAS  PubMed  Google Scholar 

  32. Kuzman JA, Vogelsang KA, Thomas TA, Gerdes AM (2005) l-Thyroxine activates Akt signalling in the heart. J Mol Cell Cardiol 39:251–258

    Article  CAS  PubMed  Google Scholar 

  33. Kuzman JA, Gerdes AM, Kobayashi S, Liang Q (2005) Thyroid hormone activates Akt and prevents serum starvation-induced cell death in neonatal rat cardiac myocytes. J Mol Cell Cardiol 39:841–844

    Article  CAS  PubMed  Google Scholar 

  34. Hartong R, Wang N, Kurokawa R, Lazar MA, Glass CK, Apriletti JW, Dillmann WH (1994) Delineation of three different thyroid hormone-response elements in promoter of rat sarcoplasmic reticulum Ca2+ ATPase gene. Demonstration that retinoid X receptor binds 5′ to thyroid hormone receptor in response element 1. J Biol Chem 269:13021–13029

    CAS  PubMed  Google Scholar 

  35. Kinugawa K, Yonekura K, Ribeiro RC, Eto Y, Aoyagi T, Baxter JD, Camacho SA, Bristow MR, Long CS, Simpson PC (2001) Regulation of thyroid hormone receptor isoforms in physiological and pathological cardiac hypertrophy. Circ Res 89:591–598

    Article  CAS  PubMed  Google Scholar 

  36. Moeller LC, Dumitrescu AM, Refetoff S (2005) Cytosolic action of thyroid hormone leads to induction of hypoxia-inducible factor-1alpha and glycolytic genes. Mol Endocrinol 19:2955–2963

    Article  CAS  PubMed  Google Scholar 

  37. Lin HY, Zhang S, West BL, Tang HY, Passaretti T, Davis FB, Davis PJ (2003) Identification of the putative MAP kinase docking site in the thyroid hormone receptor-beta1 DNA-binding domain: functional consequences of mutations at the docking site. Biochemistry 42:7571–7579

    Article  CAS  PubMed  Google Scholar 

  38. Chen SL, Chang YJ, Wu YH, Lin KH (2003) Mitogen-activated protein kinases potentiate thyroid hormone receptor transcriptional activity by stabilizing its protein. Endocrinology 144:1407–1419

    Article  CAS  PubMed  Google Scholar 

  39. Cao X, Kambe F, Yamauchi M, Seo H (2009) Thyroid hormone-dependent activation of the phosphoinositide 3-kinase/Akt cascade requires Src and enhances neuronal survival. Biochem J 424:201–209

    Article  CAS  PubMed  Google Scholar 

  40. Lin HY, Sun M, Tang HY, Lin C, Luidens MK, Mousa SA, Incerpi S, Drusano GL, Davis FB, Davis PJ (2009) l-Thyroxine vs. 3,5,3′-triiodo-l-thyronine and cell proliferation: activation of mitogen-activated protein kinase and phosphatidylinositol 3-kinase. Am J Physiol Cell Physiol 296:C980–C991

    Article  CAS  PubMed  Google Scholar 

  41. Kenessey A, Sullivan EA, Ojamaa K (2006) Nuclear localization of protein kinase C-alpha induces thyroid hormone receptor-alpha1 expression in the cardiomyocyte. Am J Physiol Heart Circ Physiol 290:H381–H389

    Article  CAS  PubMed  Google Scholar 

  42. Wang B, Ouyang J, Xia Z (2006) Effects of triiodo-thyronine on angiotensin-induced cardiomyocyte hypertrophy: reversal of increased beta-myosin heavy chain gene expression. Can J Physiol Pharmacol 84:935–941

    Article  CAS  PubMed  Google Scholar 

  43. Kuzman JA, Tang Y, Vogelsang KA, Said S, Anderson BE, Morkin E, Gerdes AM (2007) Thyroid hormone analog, diiodothyropropionic acid (DITPA), exerts beneficial effects on chamber and cellular remodeling in cardiomyopathic hamsters. Can J Physiol Pharmacol 85:311–318

    Article  CAS  PubMed  Google Scholar 

  44. Matsui T, Rosenzweig A (2005) Convergent signal transduction pathways controlling cardiomyocyte survival and function: the role of PI3-kinase and Akt. J Mol Cell Cardiol 38:63–71

    Article  CAS  PubMed  Google Scholar 

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Acknowledgments

This study was supported by grants from the Greek Ministry of Education (PYTHAGORAS II) and the General Secretariat of Research and Technology (PENED 2003).We thank Dr. D. Sanoudou for the generous gift of SERCA2α antibody.

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Authors and Affiliations

  1. Laboratory of Developmental Biology, School of Biology, Aristotle University of Thessaloniki, 54124, Thessaloniki, Greece

    Anna Iordanidou & Margarita Hadzopoulou-Cladaras

  2. Laboratory of Animal Physiology, School of Biology, Aristotle University of Thessaloniki, 54124, Thessaloniki, Greece

    Anna Iordanidou & Antigone Lazou

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  1. Anna Iordanidou
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  2. Margarita Hadzopoulou-Cladaras
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  3. Antigone Lazou
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Correspondence to Antigone Lazou.

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Iordanidou, A., Hadzopoulou-Cladaras, M. & Lazou, A. Non-genomic effects of thyroid hormone in adult cardiac myocytes: relevance to gene expression and cell growth. Mol Cell Biochem 340, 291–300 (2010). https://doi.org/10.1007/s11010-010-0430-9

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  • DOI: https://doi.org/10.1007/s11010-010-0430-9

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