Thyroid Hormone and Vascular Remodeling in Heart

  • Silvana BalzanEmail author
  • Valter Lubrano


Thyroid hormones (TH) play an important role in heart vascular system, and both hyperthyroidism and hypothyroidism are associated with altered cardiovascular system. Moreover, several evidences suggest that heart diseases trigger a reduction in cardiac tissue thyroid hormone levels.

This chapter summarizes the beneficial effects of TH on vascular remodeling of heart, analyzing the most important pillars involved in this process: thyroid receptors (TRα and TRβ), angiogenesis, nitric oxide (NO), reactive oxygen species (ROS), renin angiotensin system (RAS), and hyperlipidemia. TH actions occur largely through binding to TRα and TRβ receptors and particularly TRα-reduced vascular contractility of coronary arteries. Triiodothyronine (T3), the biologically active TH, has been found to induce angiogenesis in heart of hypothyroid mice and in rat aorta after 3 days ischemia reperfusion. TH stimulates angiogenesis through transduction of the extracellular kinase ERK 1/2 and AKT signals and transcription of angiogenic genes. Hypothyroidism shows endothelial dysfunction with a reduction in NO, whereas TH therapy improves it, reducing arterial stiffness. A decrease in ROS and NADPH oxidase activity was observed in ventricles and aortic tissue of myocardial infarcted rats treated with TH. Angiotensin type 1 receptor (AT1R) that is involved in vascular remodeling has been observed downregulated in the aorta in hyperthyroidism. Finally, in hypothyroidism, intima-media thickness (IMT) of the carotid artery was significantly higher than that in control and improved after treatment with levothyroxine. In conclusion, this chapter underlines the role of TH in heart vascular remodeling.


Thyroid hormone Angiogenesis Reactive oxygen species Nitric oxide Renin angiotensin system Hyperlipidemia Heart vascular remodeling 


  1. 1.
    Ichiki T. Thyroid hormone and vascular remodeling. J Atheroscler Thromb. 2016;23:266–75. Scholar
  2. 2.
    Cappola AR, Landenson PW. Hypothyroidism and atherosclerosis. J Clin Endocrinol and Metab. 2003;88:2438–44. Scholar
  3. 3.
    Hak AE, Pols HA, Visser TJ, Drexhage HA, Hofman A, Witteman JC. Subclinical hypothyroidism is an independent risk factor for atherosclerosis and myocardial infarction in elderly women: the Rotterdam Study. Ann Intern Med. 2000;132:270–8.CrossRefGoogle Scholar
  4. 4.
    Weltman NY, Ojamaa K, Schlenker EH, Chen YF, Zucchi R, Saba A, et al. Low-dose T3 replacement restores depressed cardiac T3 levels, preserves coronary microvasculature, and attenuates cardiac dysfunction in experimental diabetes mellitus. Mol Med. 2014;20:302–12. Scholar
  5. 5.
    Karch R, Neumann F, Ullrich R, Neumüller J, Podesser BK, Neumann M, et al. The spatial pattern of coronary capillaries in patients with dilated, ischemic, or inflammatory cardiomyopathy. Cardiovasc Pathol. 2005;14:135–44. Scholar
  6. 6.
    Nicolini G, Pitto L, Kusmic C, Balzan S, Sabatino L, Iervasi G, et al. New insights into mechanisms of cardioprotection mediated by thyroid hormones. J Thyroid Res. 2013;2013:264387. Scholar
  7. 7.
    Gerdes AM, Ojamaa K. Thyroid hormone and cardioprotection. Compr Physiol. 2016;6:1199219. Scholar
  8. 8.
    Rajagopalan V, Zhang Y, Ojamaa K, Chen YF, Pingitore A, Pol CJ, et al. Safe oral triiodo-L-thyronine therapy protects from post-infarct cardiac dysfunction and arrhythmias without cardiovascular adverse effects. PLoS One. 2016;11:e0151413. Scholar
  9. 9.
    Iervasi G, Nicolini G. Thyroid hormone and cardiovascular system: from basic concepts to clinical application. Intern Emerg Med. 2013;8:S71–4. Scholar
  10. 10.
    Forini F, Kusmic C, Nicolini G, Mariani L, Zucchi R, Matteucci M, et al. Triiodothyronine prevents cardiac ischemia/reperfusion mitochondrial impairment and cell loss by regulating miR30a/p53 axis. Endocrinology. 2014;155:4581–90. Scholar
  11. 11.
    Nicolini G, Forini F, Kusmic C, Pitto L, Mariani L, Iervasi G. Early and short-term triiodothyronine supplementation prevents adverse post-ischemic cardiac remodeling: role of transforming growth factor-β1 and anti-fibrotic miRNA signaling. Mol Med. 2016;21:900–11. Scholar
  12. 12.
    Gerdes AM. Restoration of thyroid hormone balance: a game changer in the treatment of heart failure? Am J Physiol Heart Circ Physiol. 2015;308:H1–10. Scholar
  13. 13.
    de Castro AL, Tavares AV, Fernandes RO, Campos C, Conzatti A, Siqueira R, et al. T3 and T4 decrease ROS levels and increase endothelial nitric oxide synthase expression in the myocardium of infarcted rats. Mol Cell Biochem. 2015;408:235–43. Scholar
  14. 14.
    Renna NF, de Las Heras N, Miatello RM. Pathophysiology of vascular remodeling in hypertension. Int J Hypertens. 2013; Article ID 808353, 7 pages. Scholar
  15. 15.
    Liu Y, Sherer BA, Redetzke RA, Gerdes AM. Regulation of arteriolar density in adult myocardium during low thyroid conditions. Vasc Pharmacol. 2010;52:146–50. Scholar
  16. 16.
    Chen J, Ortmeier SB, Savinova OV, Nareddy VB, Beyer AJ, Wang D, et al. Thyroid hormone induces sprouting angiogenesis in adult heart of hypothyroid mice through the PDGF-Akt pathway. J Cell Mol Med. 2012;16:2726–35. Scholar
  17. 17.
    Rodríguez-Gómez I, Banegas I, Wangensteen R, Quesada A, Jiménez R, Gómez-Morales M, et al. Influence of thyroid state on cardiac and renal capillary density and glomerular morphology in rats. J Endocrinol. 2013;216:43–51. Scholar
  18. 18.
    Savinova OV, Yingheng Liu, Aasen GA, Mao Kai, Weltman NY, Nedich BL, et al. Low thyroid hormone (TH) function has been linked to impaired coronary blood flow, reduced density of small arterioles, and heart failure. PLoS One. 2011;6. Article ID e25054. Scholar
  19. 19.
    Sabatino L, Kusmic C, Nicolini G, Amato R, Casini G, Iervasi G, et al. T3 enhances Ang2 in rat aorta in myocardial I/R: comparison with left ventricle. J Mol Endocrinol. 2016;57:139–49. Scholar
  20. 20.
    Ren G, Michael LH, Entman ML, Frangogiannis NG. Morphological characteristics of the microvasculature in healing myocardial infarcts. J Histochem Cytochem. 2002;50:71–9. Scholar
  21. 21.
    Diekman MJ, Zandieh Doulabi B, Platvoet-Ter Schiphorst M, Fliers E, Bakker O, Wiersinga WM. The biological relevance of thyroid hormone receptors in immortalized human umbilical vein endothelial cells. J Endocrinol. 2001;68:427–33.CrossRefGoogle Scholar
  22. 22.
    Makino A, Suarez J, Wang H, Belke DD, Scott BT, Dillmann WH. Thyroid hormone receptor-beta is associated with coronary angiogenesis during pathological cardiac hypertrophy. Endocrinology. 2009;150:2008–15. Scholar
  23. 23.
    Makino A, Wang H, Scott BT, Yuan JX, Dillmann WH. Thyroid hormone receptor-α and vascular function. Am J of Physiol. 2012;302:C1346–52. Scholar
  24. 24.
    Gloss B, Trost S, Bluhm W, Swanson E, Clark R, Winkfein R, et al. Cardiac ion channel expression and contractile function in mice with deletion of thyroid hormone receptor-α or -β. Endocrinology. 2001;142:544–50. Scholar
  25. 25.
    Hiroi Y, Kim HH, Ying H, Furuya F, Huang Z, Simoncini T, et al. Rapid nongenomic actions of thyroid hormone. Proc Natl Acad Sci U S A. 2006;103:14104–9. Scholar
  26. 26.
    Suarez J, Wang H, Scott BT, Ling H, Makino A, Swanson E, et al. In vivo selective expression of thyroid hormone receptor α1 in endothelial cells attenuates myocardial injury in experimental myocardial infarction in mice. Am J Physiol Regul Integr Comp Physiol. 2014;307:R340–6. Scholar
  27. 27.
    Pantos C, Mourouzis I, Saranteas T, Paizis I, Xinaris C, Malliopoulou V, et al. Thyroid hormone receptors alpha1 and beta1 are downregulated in the post-infarcted rat heart: consequences on the response to ischaemia-reperfusion. Basic Res Cardiol. 2005;100:422–32. Scholar
  28. 28.
    Olivares EL, Marassi MP, Fortunato RS, Da Silva ACM, Costa-E-Sousa RH, Araújo IG, et al. Thyroid function disturbance and type 3 iodothyronine deiodinase induction after myocardial infarction in rats—a time course study. Endocrinology. 2007;148:4786–92. Scholar
  29. 29.
    Pantos C, Mourouzis I. Thyroid hormone receptor α1 as a novel therapeutic target for tissue repair. Ann Transl Med. 2018;6:254. Scholar
  30. 30.
    Ortiz VD, de Castro AL, Camposa C, Fernandesa RO, Bonettoa J, Siqueiraa R, et al. Effects of thyroid hormones on aortic tissue after myocardial infarction in rats. Eur J of Pharmacol. 2016;791:788–93. Scholar
  31. 31.
    Kim ES, Shin JA, Shin JY, Lim DJ, Moon SD, Son HY, et al. Association between low serum free thyroxine concentrations and coronary artery calcification in healthy euthyroid subjects. Thyroid. 2012;22:870–6. Scholar
  32. 32.
    Sato Y, Nakamura R, Satoh M, Fujishita K, Mori S, Ishida S, et al. Thyroid hormone targets matrix Gla protein gene associated with vascular smooth muscle calcification. Circ Res. 2005;97:550–7. Scholar
  33. 33.
    Tomanek RJ, Schatteman GC. Angiogenesis: new insights and therapeutic potential. Anat Rec. 2000;261:126–35.CrossRefGoogle Scholar
  34. 34.
    Kessler K, Borges LF, Ho-Tin-Noé B, Jondeau G, Michel JB, Vranckx R. Angiogenesis and remodelling in human thoracic aortic aneurysms. Cardiovasc Res. 2014;104:147–59. Scholar
  35. 35.
    Davis PJ, Davis FB, Mousa SA. Thyroid hormone-induced angiogenesis. Curr Cardiol Rev. 2009;5:12–6. Scholar
  36. 36.
    Balzan S, Del Carratore R, Nardulli C, Sabatino L, Lubrano V, Iervasi G. The stimulative effect of T3 and T4 on human myocardial endothelial cell proliferation, migration and angiogenesis. J Clin Exp Cardiol. 2013;4:1–7. Scholar
  37. 37.
    Moeller LC, Broecker-Preuss M. Transcriptional regulation by non classical action of thyroid hormone. Thyroid Res. 2011;4:S6. Scholar
  38. 38.
    Davis FB, Mousa SA, O’Connor L, Mohamed S, Lin HY, Cao HJ, et al. Proangiogenic action of thyroid hormone is fibroblast growth factor-dependent and is initiated at the cell surface. Circ Res. 2004;94:1500–6. Scholar
  39. 39.
    Mousa SA, Bergh JJ, Dier E, Rebbaa A, O’Connor LJ, Yalcin M, et al. Tetraiodothyroacetic acid, a small molecule integrin ligand, blocks angiogenesis induced by vascular endothelial growth factor and basic fibroblast growth factor. Angiogenesis. 2008;11:183–90. Scholar
  40. 40.
    Lin HY, Davis FB, Gordinier JK, Martino LJ, Davis PJ. Thyroid hormone induces activation of mitogen activated protein kinase in cultured cells. Am J Phys. 1999;276:C1014–24.CrossRefGoogle Scholar
  41. 41.
    Shih A, Lin HY, Davis FB, Davis PJ. Thyroid hormone promotes serine phosphorylation of p53 by mitogen-activated protein kinase. Biochemistry. 2001;40:2870–8.CrossRefGoogle Scholar
  42. 42.
    Luidens MK, Mousa SA, Davis FB, Lin HY, Davis PJ. Thyroid hormone and angiogenesis. Vasc Pharmacol. 2010;52:142–5. Scholar
  43. 43.
    Taimeh Z, Loughran J, Birks EJ, Bolli R. Vascular endothelial growth factor in heart failure. Nat Rev Cardiol. 2013;10:519–30. Scholar
  44. 44.
    Forini F, Lionetti V, Ardehali H, Pucci A, Cecchetti F, Ghanefar M, et al. Early long-term L-T3 replacement rescues mitochondria and prevents ischemic cardiac remodelling in rats. J Cell Mol Med. 2011;15:514–24. Scholar
  45. 45.
    Eckle T, Kohler D, Lehmann R, Kasmi KCE, Eltzschig HK. Hypoxia-inducible factor-1 is central to cardioprotection a new paradigm for ischemic preconditioning. Circulation. 2008;118:166–75.CrossRefGoogle Scholar
  46. 46.
    Moeller LC, Dumitrescu AM, Refetoff S. Cytosolic action of thyroid hormone leads to induction of hypoxia-inducible factor-1α and glycolytic genes. Mol Endocrinol. 2005;19:2955–63. Scholar
  47. 47.
    Furuya F, Hanover JA, Cheng SY. Activation of phosphatidylinositol 3-kinase signaling by a mutant thyroid hormone β receptor. Proc Natl Acad Sci U S A. 2006;103:1780–5. Scholar
  48. 48.
    Thomas M, Augustin HG. The role of the angiopoietins in vascular morphogenesis. Angiogenesis. 2009;12:125–37. Scholar
  49. 49.
    Fiedler U, Reiss Y, Scharpfenecker M, Grunow V, Koidl S, Thurston G, et al. Angiopoietin-2 sensitizes endothelial cells to TNF-alpha and has a crucial role in the induction of inflammation. Nat Med. 2006;12:235–9. Scholar
  50. 50.
    Lee SW, Won JY, Lee HY, Lee HJ, Youn SW, Lee JY, et al. Angiopoietin-1 protects heart against ischemia/reperfusion injury through VE-cadherin dephosphorylation and myocardiac integrin-β1/ERK/caspase-9 phosphorylation cascade. Mol Med. 2011;17:1095–106. Scholar
  51. 51.
    Wang X, Zheng W, Christensen LP, Tomanek RJ. DITPA stimulates bFGF, VEGF, angiopoietin, and Tie-2 and facilitates coronary arteriolar growth. Am J Physiol Heart Circ Physiol. 2003;284:H613–8. Scholar
  52. 52.
    Zheng W, Weiss RM, Wang X, Zhou R, Arlen AM, Lei L, et al. DITPA stimulates arteriolar growth and modifies myocardial post infarction remodeling. Am J Physiol Heart Circ Physiol. 2004;286:H1994–2000. Scholar
  53. 53.
    Lekakis J, Papamichael C, Alevizaki M, Piperingos G, Marafelia P, Mantzos J, et al. Flow-mediated, endothelium-dependent vasodilation is impaired in subjects with hypothyroidism, borderline hypothyroidism, and high-normal serum thyrotropin (TSH) values. Thyroid. 1997;7:411–4. Scholar
  54. 54.
    Papaioannou GI, Lagasse M, Mather JF, Thompson PD. Treating hypothyroidism improves endothelial function. Metabolism. 2004;53:278–9. Scholar
  55. 55.
    Alibaz Oner F, Yurdakul S, Oner E, Kubat Uzum A, Erguney M. Evaluation of the effect of L-thyroxin therapy on endothelial functions in patients with subclinical hypothyroidism. Endocrine. 2011;40:280–4. Scholar
  56. 56.
    Jabbar A, Pingitore A, Pearce SH, Zaman A, Iervasi G, Razvi S. Thyroid hormones and cardiovascular disease. Nat Rev Cardiol. 2017;14(1):39–55. Scholar
  57. 57.
    Razvi S, Jabbar A, Pingitore A, Danzi S, Biondi B, Klein I, et al. Thyroid hormones and cardiovascular function and diseases. J Am Coll Cardiol. 2018;71:1781–96. Scholar
  58. 58.
    Taddei S, Caraccio N, Virdis A, Dardano A, Versari D, Ghiadoni L, et al. Impaired endothelium-dependent vasodilatation in subclinical hypothyroidism: beneficial effect of levothyroxine therapy. J Clin Endocrinol Metab. 2003;88:3731–7. Scholar
  59. 59.
    Bedard K, Krause KH. The NOX family of ROS-generating NADPH oxidases: physiology and pathophysiology. Physiol Rev. 2007;87:245–313. Scholar
  60. 60.
    Lassègue B, Griendling KK. NADPH oxidases: functions and pathologies in the vasculature. Arterioscler Thromb Vasc Biol. 2010;30:653–61. Scholar
  61. 61.
    Jackson MJ, Papa S, Bolaños J, Bruckdorfer R, Carlsen H, Elliott RM, et al. Antioxidants, reactive oxygen nitrogen species, gene induction and mitochondrial function. Mol Asp Med. 2002;23:209–85. Scholar
  62. 62.
    Manea A. NADPH oxidase-derived reactive oxygen species: involvement in vascular physiology and pathology. Cell Tissue Res. 2010;342:325–39. Scholar
  63. 63.
    Konior A, Schramm M, Czesnikiewicz-Guzik TJ, Guzik TJ. NADPH oxidases in vascular pathology. Antioxid Redox Signal. 2014;20:2794–814. Scholar
  64. 64.
    de Castro AL, Tavares AV, Campos C, Oliveira RO, Siqueira R, Conzatti A, et al. Cardioprotective effects of thyroid hormones in a rat model of myocardial infarction are associated with oxidative stress reduction. Mol Cell Endocrinol. 2014;391:22–9. Scholar
  65. 65.
    Gnocchi D, Leoni S, Incerpi S, Bruscalupi G. 3,5,3′-triiodothyronine (T3) stimulates cell proliferation through the activation of the PI3K/Akt pathway and reactive oxygen species (ROS) production in chick embryo hepatocytes. Steroids. 2012;77:589–95. Scholar
  66. 66.
    Verga Falzacappa C, Petrucci E, Patriarca V, Michienzi S, Stigliano A, Brunetti E, et al. Thyroid hormone receptor TRbeta1 mediates Akt activation by T3 in pancreatic beta cells. J Mol Endocrinol. 2007;38:221–33. Scholar
  67. 67.
    Kowalik MA, Perra A, Pibiri M, Cocco MT, Samarut J, Plateroti M, et al. TR-beta is the critical thyroid hormone receptor isoform in T3-induced proliferation of hepatocytes and pancreatic acinar cells. J Hepatol. 2010;53:686–92. Scholar
  68. 68.
    Wang X, Sun Z. Thyroid hormone induces artery smooth muscle cell proliferation: discovery of a new TRα1-Nox1 pathway. J Cell Mol Med. 2010;14:368–80. Scholar
  69. 69.
    Dzau VJ. Mechanism of protective effects of ACE inhibition on coronary artery disease. Eur Heart J. 1998;19:J2–6.PubMedGoogle Scholar
  70. 70.
    Geisterfer AA, Peach MJ, Owens GK. Angiotensin II induces hypertrophy, not hyperplasia, of cultured rat aortic smooth muscle cells. Circ Res. 1988;62:749–56.CrossRefGoogle Scholar
  71. 71.
    Resnick LM, Laragh JH. Plasma renin activity in syndromes of thyroid hormone excess and deficiency. Life Sci. 1982;30:585–6.CrossRefGoogle Scholar
  72. 72.
    Carrillo-Sepulveda MA, Ceravolo GS, Furstenau CR, Monteiro Pde S, Bruno-Fortes Z, Carvalho MH, et al. Emerging role of angiotensin type 2 receptor (AT2R)/Akt/NO pathway in vascular smooth muscle cell in the hyperthyroidism. PLoS One. 2013;8:e61982. Scholar
  73. 73.
    Fukuyama K, Ichiki T, Imayama I, Ohtsubo H, Ono H, Hashiguchi Y, et al. Thyroid hormone inhibits vascular remodeling through suppression of cAMP response element binding protein activity. Arterioscler Thromb Vasc Biol. 2006;26:2049–55. Scholar
  74. 74.
    Viswanathan M, Strömberg C, Seltzer A, Saavedra JM. Balloon angioplasty enhances the expression of angiotensin II AT1 receptors in neointima of rat aorta. J Clin Invest. 1992;90:1707–12.CrossRefGoogle Scholar
  75. 75.
    Kauffman RF, Bean JS, Zimmerman KM, Brown RF, Steinberg MI. Losartan, a nonpeptide angiotensin II (Ang II) receptor antagonist, inhibits neointima formation following balloon injury to rat carotid arteries. Life Sci. 1991;49:PL223–8.CrossRefGoogle Scholar
  76. 76.
    Fukuyama K, Ichiki T, Takeda K, Tokunou T, Iino N, Masuda S, et al. Downregulation of vascular angiotensin II type 1 receptor by thyroid hormone. Hypertension. 2003;41:598–603. Scholar
  77. 77.
    Carneiro-Ramos MS, Silva VB, Santos RA, Barreto-Chaves ML. Tissue-specific modulation of angiotensin-converting enzyme (ACE) in hyperthyroidism. Peptides. 2006;27:2942–9. Scholar
  78. 78.
    Sundaram V, Hanna AN, Koneru L, Newman HA, Falko JM. Both hypothyroidism and hyperthyroidism enhance low density lipoprotein oxidation. J Clin Endocrinol Metab. 1997;82:3421–4.PubMedGoogle Scholar
  79. 79.
    Nagasaki T, Inaba M, Henmi Y, Kumeda Y, Ueda M, Tahara H, et al. Decrease in carotid intima-media thickness in hypothyroid patients after normalization of thyroid function. Clin Endocrinol. 2003;59:607–12.CrossRefGoogle Scholar
  80. 80.
    Singh S, Duggal J, Molnar J, Maldonado F, Barsano CP, Arora R. Impact of subclinical thyroid disorders on coronary heart disease, cardiovascular and all-cause mortality: a meta-analysis. Int J Cardiol. 2008;125:41–8. Scholar
  81. 81.
    Quan X, Ji Y, Zhang C, Guo X, Zhang Y, Jia S, et al. Circulating MiR-146a may be a potential biomarker of coronary heart disease in patients with subclinical hypothyroidism. Cell Physiol Biochem. 2018;45(1):226–36. Scholar
  82. 82.
    Mizuma H, Murakami M, Mori M. Thyroid hormone activation in human vascular smooth muscle cells: expression of type II iodothyronine deiodinase. Circ Res. 2001;88:313–8.CrossRefGoogle Scholar
  83. 83.
    Goyal T, Mitra S, Khaidakov M, Wang X, Singla S, Ding Z, et al. Current concepts of the role of oxidized LDL receptors in atherosclerosis. Curr Atheroscler Rep. 2012;14:150–9. Scholar
  84. 84.
    Twigg MW, Freestone K, Homer-Vanniasinkam S, Ponnambalam S. The LOX-1 scavenger receptor and its implications in the treatment of vascular disease. Cardiol Res Pract. 2012;2012:632408. Scholar
  85. 85.
    Vicinanza R, Coppotelli G, Malacrino C, Nardo T, Buchetti B, Lenti L, et al. Oxidized low-density lipoproteins impair endothelial function by inhibiting non-genomic action of thyroid hormone–mediated nitric oxide production in human endothelial cells. Thyroid. 2013;23:231–8. Scholar
  86. 86.
    Balzan S, Sabatino L, Lubrano V. Lectin-like oxidized low-density lipoprotein receptor (Lox-1), thyroid hormone (T3) and reactive oxygen species (Ros): possible cross-talk in angiogenesis. Theor Biol Forum. 2017;110:13–23. Scholar

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Authors and Affiliations

  1. 1.Institute of Clinical Physiology, CNRPisaItaly
  2. 2.Fondazione CNR/Regione Toscana G. MonasterioPisaItaly

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