Nongenomic effects of thyroid hormones: role in regulation of the vascular system
Abstract
The nongenomic effects of thyroid hormones develop within minutes or hours and do not depend on the binding of the hormone to the transcriptionally active nuclear receptors TRα and TRβ. These effects are characterized by a variety of receptors and signaling pathways involved, which may be distinct in different cell types. T3 or T4 can induce nongenomic effect by association with transcriptionally inactive TRα and TRβ in the cytoplasm of the cell, their truncated isoforms or integrin αvβ3. With nongenomic action, as well as with genomic action, T3 and T4 can alter gene transcription, but in this case, their influence is extended to wider spectrum of genes. The nongenomic effects of thyroid hormones often complement the genomic ones, causing similar changes in cell activity, or enhance them by providing TRα and TRβ translocation into the nucleus or their post-translational modification. The nongenomic effects of thyroid hormones on the vasculature include angiogenesis and rapid vasodilation. The key signaling cascade mediating angiogenesis includes integrin αvβ3, protein kinase D, and histone deacetylase 5. The mechanisms of rapid vasodilation are still poorly understood and may vary in different regions of the vascular bed. In cytoplasm of endothelial cells, the nongenomic effect of thyroid hormones is mediated by TRα1, PI3K, and NO synthase, but this mechanism is not universal. Thyroid hormones-induced vasodilation of skeletal muscle arteries includes the participation of αvβ3 integrin located in smooth muscle cells, but the signaling cascades triggered by it have not yet been studied. Knowledge of the molecular mechanisms of the nongenomic effect of thyroid hormones is important for the development of new methods of pharmacological correction of vascular pathologies, which are usually associated with thyroid disorders.
About the Authors
E. K. Selivanova
Department of Human and Animal Physiology, Faculty of Biology, Lomonosov Moscow State University
Russian Federation
Leninskiye gory 1–12, Moscow, 119234
Russian Federation
Leninskiye gory 1–12, Moscow, 119234
O. S. Tarasova
Department of Human and Animal Physiology, Faculty of Biology, Lomonosov Moscow State University; Laboratory of Exercise Physiology, Institute for Biomedical Problems, Russian Academy of Sciences
Russian Federation
Russian Federation
Leninskiye gory 1–12, Moscow, 119234
Khoroshevskoye shosse 76A, Moscow, 123007
References
1. Hulbert A.J. Thyroid hormones and their effects: a new perspective // Biol. Rev. 2000. Vol. 75. N 4. P. 519–631.
2. Vasudevan N., Ogawa S., Pfaff D. Estrogen and thyroid hormone receptor interactions: physiological flexibility by molecular specificity // Physiol. Rev. 2002. Vol. 82. N 4. P. 923–944.
3. Vassy R.. Nicolas P., Yin Y.L., Perret G.Y. Nongenomic effect of triiodothyronine on cell surface betaadrenoceptors in cultured embryonic cardiac myocytes // Proc. Soc. Exp. Biol. Med. 1997. Vol. 214. N 4. P. 352–358.
4. Hammes S.R., Davis P.J. Overlapping nongenomic and genomic actions of thyroid hormone and steroids // Best Pract. Res. Clin. Endocrinol. Metab. 2015. Vol. 29. N 4. P. 581–593.
5. Davis P.J., Davis F.B., Lin H.Y., Mousa S.A., Zhou M., Luidens M.K. Translational implications of nongenomic actions of thyroid hormone initiated at its integrin receptor // Am. J. Physiol. Endocrinol. Metab. 2009. Vol. 297. N 6. P. E1238–E1246.
6. Flamant F., Cheng S., Hollenberg A., Moeller L.C., Samarut J., Wondisford F.E., Yen P.M., Refetoff S. Thyroid hormone signaling pathways: Time for a more precise nomenclature // Endocrinology. 2017. Vol. 158. N 7. P. 2052–2057.
7. Davis P.J., Leonard, J.L., Lin H.Y., Leinung M., Mousa S.A. Molecular basis of nongenomic actions of thyroid hormone // Vitam. Horm. 2018. Vol. 106. P. 67–96.
8. Louzada R.A., Carvalho D.P. Similarities and differences in the peripheral actions of thyroid hormones and their metabolites // Front. Endocrinol. 2018. Vol. 9: 394
9. Schroeder A., Jimenez R., Young B., Privalsky M.L. The ability of thyroid hormone receptors to sense T4 as an agonist depends on receptor isoform and on cellular cofactors // Mol. Endocrinol. 2014. Vol. 28. N 5. P. 745–757.
10. Cao X., Kambe F., Moeller L.C., Refetoff S., Seo H. 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. 2005. Vol. 19. N 1. P. 102–112.
11. Moeller L.C., Dumitrescu A.M., Refetoff S. Cytosolic action of thyroid hormone leads to induction of hypoxiainducible factor-1α and glycolytic genes // Mol. Endocrinol. 2005. Vol. 19. N 12. P. 2955–2963.
12. Hiroi Y., Kim H.H., Ying H., Furuya F., Huang Z., Simoncini T., Noma K., Ueki K., Nguyen N., Scanlan T.S., Moskowitz M.A., Cheng S.Y., Liao J.K. Rapid nongenomic actions of thyroid hormone // Proc. Natl. Acad. Sci. U.S.A. 2006. Vol. 103. N 38. P. 14104–14109.
13. Plateroti M., Gauthier K., Domon-Dell C., Freund J., Samarut J., Chassande O. Functional interference between thyroid hormone receptor alpha (TRalpha) and natural truncated TRDeltaalpha isoforms in the control of intestine development // Mol. Cell. Biol. 2001. Vol. 21. N 14. P. 4761–4772.
14. Chassande O., Fraichard A., Gauthier K., Flamant F., Legrand C., Savatier P., Laudet V., Samarut J. Identification of transcripts initiated from an internal promoter in the c-erbAα locus that encode inhibitors of retinoic acid receptor-α and triiodothyronine receptor activities // Mol. Endocrinol. 1997. Vol. 11. N 9. P. 1278–1290.
15. Siegrist-Kaiser C.A., Juge-Aubry C., Tranter M.P., Ekenbarger D.M., Leonard J.L. Thyroxine-dependent modulation of actin polymerization in cultured astrocytes. A novel, extranuclear action of thyroid hormone // J. Biol. Chem. 1990. Vol. 265. N 9. P. 5296–5302.
16. Davis P.J., Leonard J.L., Davis F.B. Mechanisms of nongenomic actions of thyroid hormone // Front. Neuroendocrinol. 2008. Vol. 29. N 2. P. 211–218.
17. Cheng S.Y., Leonard J.L., Davis P.J. Molecular aspects of thyroid hormone actions // Endocr. Rev. 2010. Vol. 31. N 2. P. 139–170.
18. Lanni A., Moreno M., Goglia F. Mitochondrial actions of thyroid hormone // Compr. Physiol. 2016. Vol. 6. N 4. P. 1591–1607.
19. Wrutniak C., Cassar-Malek I., Marchal S., Rascle A., Heusser S., Keller J., Flechon J., Dauca M., Samarut J., Ghysdael J., Cabello G. A 43-kDa protein related to c-Erb A α1 is located in the mitochondrial matrix of rat liver // J. Biol. Chem. 1995. Vol. 270. N 27. P. 16347–16354.
20. Pessemesse L., Lepourry L., Bouton K., Levin J., Cabello G., Wrutniak-Cabello C., Casas F. P28, a truncated form of TRα1 regulates mitochondrial physiology // FEBS Lett. 2014. Vol. 588. N 21. P. 4037–4043.
21. Botta J., Mendoza D., Morero R.D., Farias R.N. High affinity L-triidothyronine binding sites on washed rat erythrocyte membranes // J. Biol. Chem. 1983. Vol. 258. N 11. P. 6690–6692.
22. Lin H.Y., Davis F.B., Gordinier J.K., Martion L.J., Davis P.J. Thyroid hormone induces activation of mitogenactivated protein kinase in cultured cells // Am. J. Physiol. Cell Physiol. 1999. Vol. 276. N 5. P. C1014–C1024.
23. Kalyanaraman H., Schwappacher R., Joshua J., Zhuang S., Scott B.T., Klos M., Casteel D.E., Frangos J.A., Dillmann W., Boss G.R., Pilz R.B. Nongenomic thyroid hormone signaling occurs through a plasma membranelocalized receptor // Sci. Signal. 2014. Vol. 7. N 326: ra48.
24. Bergh J.J., Lin H., Lansing L., Mohamed S.N., Davis F.B., Mousa S., Davis P.J. Integrin αVβ3 contains a cell surface receptor site for thyroid hormone that is linked to activation of mitogen-activated protein kinase and induction of angiogenesis // Endocrinology. 2005. Vol. 146. N 7. P. 2864–2871.
25. LaFoya B., Munroe J.A., Miyamoto A., Detweiler M.A., Crow J.J., Gazdik T., Albig A.R. Beyond the matrix: The many non-ECM ligands for integrins // Int. J. Mol. Sci. 2018. Vol. 19. N 2: 449.
26. Hynes R.O. Integrins: Versatility, modulation, and signaling in cell adhesion // Cell. 1992. Vol. 69. N 1. P. 11–25.
27. Xiong J.-P., Stehle T., Zhang R., Joachimiak A., Frech M., Goodman S.L., Arnaout M.A. Crystal structure of the extracellular segment of integrin αVβ3 in complex with an Arg-Gly-Asp ligand // Science. 2002. Vol. 296. N 5565. P. 151–155.
28. Freindorf M., Furlani T.R., Kong J., Cody V., Davis F.B., Davis P.J. Combined QM/MM study of thyroid and steroid hormone analogue interactions with integrin // J. Biomed. Biotechnol. 2012. Vol. 2012: 959057.
29. Lin H.Y., Sun M., Tang H., Lin C., Luidens M.K., Mousa S.A., Incerpi S., Drusano G.L., Davis F.B., Davis P.J. 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. 2009. Vol. 296. N 5. P. C980–C991.
30. Uzair I.D., Grand J.C., Flamini M.I., Sanchez A.M. Molecular actions of thyroid hormone on breast cancer cell migration and invasion via cortactin/N-WASP // Front. Endocrinol. 2019. Vol. 10: 139.
31. Davis P.J., Shih A., Lin H., Martino L.J., Davis F.B. Thyroxine promotes association of mitogen-activated protein kinase and nuclear thyroid hormone receptor (TR) and causes serine phosphorylation of TR // J. Biol. Chem. 2000. Vol. 275. N 48. P. 38032–38039.
32. Cao H.J., Lin H., Luidens M.K., Davis F.B., Davis P.J. Cytoplasm-to-nucleus shuttling of thyroid hormone receptor-β1 (Trβ1) is directed from a plasma membrane integrin receptor by thyroid hormone // Endocr. Res. 2009. Vol. 34. N 1–2. P. 31–42.
33. Lin H., Shih A., Davis F.B., Davis P.J. Thyroid hormone promotes the phosphorylation of STAT3 and potentiates the action of epidermal growth factor in cultured cells // Biochemistry. 1999. Vol. 338. N 2. P. 427–432.
34. Liu X., Zheng N., Shi Y., Yuan J., Lanying L. Thyroid hormone induced angiogenesis through the integrin αvβ3/protein kinase D/histone deacetylase 5 signaling pathway // J. Mol. Endocrinol. 2014. Vol. 52. N 3. P. 245–254.
35. Lei J., Ingbar D.H. Src kinase integrates PI3K/Akt and MAPK/ERK1/2 pathways in T3-induced Na-KATPase activity in adult rat alveolar cells // Am. J. Physiol. Cell Mol. Physiol. 2011. Vol. 301. N 5. P. L765–L771.
36. Axelband F., Dias J., Ferrão F.M., EinickerLamas M. Nongenomic signaling pathways triggered by thyroid hormones and their metabolite 3-iodothyronamine on the cardiovascular system // J. Cell. Physiol. 2010. Vol. 226. N 1. P. 21–28.
37. Farwell A.P., Dubord-Tomasetti S.A., Pietrzykowski A.Z., Stachelek S.J., Leonard J.L. Regulation of cerebellar neuronal migration and neurite outgrowth by thyroxine and 3,3′,5′-triiodothyronine // Dev. Brain Res. 2005. Vol. 154. N 1. P. 121–135.
38. Lin H., Su Y., Hsieh M., Lin S., Meng R., London D., Lin C., Tang H., Hwang J., Davis F.B., Mousa S.A., Davis P.J. Nuclear monomeric integrin αv in cancer cells is a coactivator regulated by thyroid hormone // FASEB J. 2013. Vol. 27. N 8. P. 3209–3216.
39. Oliveira M., Olimpio R.M.C, Sibio M.T., Moretto F.C.F., Luvizotto R.A.M.. Nogueira C.R. Short-term effects of triiodothyronine on thyroid hormone receptor alpha by PI3K pathway in adipocytes, 3T3-L1 // Arq. Bras. Endocrinol. Metabol. 2014. Vol. 58. N 8. P. 833–837.
40. Lin H.-Y., Hopkins R., Cao H.J., Tang H., Alexander C., Davis F.B., Davis P.J. Acetylation of nuclear hormone receptor superfamily members: thyroid hormone causes acetylation of its own receptor by a mitogen-activated protein kinase-dependent mechanism // Steroids. 2005. Vol. 70. N 5–7. P. 444–449.
41. Sánchez-Pacheco A., Martinez-Iglesias O., MendezPertuz M., Aranda A. Residues K128, 132, and 134 in the thyroid hormone receptor-α are essential for receptor acetylation and activity // Endocrinology. 2009. Vol. 150. N 11. P. 5143–5152.
42. Scapin S., Leoni S., Spagnuolo S., Gnocchi D., De Vito P., Luly P., Pedersen J.Z., Incerpi S. Short-term effects of thyroid hormones during development: Focus on signal transduction // Steroids. 2010. Vol. 75. N 8–9. P. 576–584.
43. Danzi S., Klein I. Thyroid disease and the cardiovascular system // Endocrinol. Metab. Clin. 2014. Vol. 43. N 2. P. 517–528.
44. Vargas F., Moreno J.M., Rodriguez-Gomez I., Wangensteen R., Osuna A., Alvarez-Guerra M., GarcisEstan J. Vascular and renal function in experimental thyroid disorders // Eur. J. Endocrinol. 2006. Vol. 154. N 2. P. 197–212.
45. Heron M.I., Rakusan K. Short- and long-term effects of neonatal hypo- and hyperthyroidism on coronary arterioles in rat // Am. J. Physiol. 1996. Vol. 271. N 5. P. H1746–H1754.
46. Rodriguez-Gomez I., Banegas I., Wangensteen R., Quesada A., Jimenez R., Gomez-Morales M., Francisco O’Valle, Duarte J., Vargas F. Influence of thyroid state on cardiac and renal capillary density and glomerular morphology in rats // J. Endocrinol. 2013. Vol. 216. N 1. P. 43–51.
47. Селиванова Е.К., Тарасова О.С. Программирующее влияние тиреоидных гормонов на сердечно-сосудистую систему // Валеология. 2016. № 4. С. 60–67.
48. Тарасова О.С., Софронова С.И., Гайнуллина Д.Г., Борзых А.А., Мартьянов А.А. Регуляция продукции оксида азота эндотелием сосудов при физической нагрузке: роль тиреоидных гормонов // Авиакосм. эколог. мед. 2015. Т. 49. № 2. С. 55–62.
49. McAllister R.M., Grossenburg V. D., Delp M.D., Laughlin M.H. Effects of hyperthyroidism on vascular contractile and relaxation responses // Am. J. Physiol. Endocrinol. Metab. 1998. Vol. 274. N 5. P. E946–E953.
50. Khorshidi-Behzadi M., Alimoradi H., HaghjooJavanmard S., Sharifi M.R., Rahimi N., Dehpour A.R. The effect of chronic hyperthyroidism and restored euthyroid state by methimazole therapy in rat small mesenteric arteries // Eur. J. Pharmacol. 2013. Vol. 701. N 1–3. P. 20–26.
51. Honda H., Iwata T., Mochizuki T., Kogo H. Changes in vascular reactivity induced by acute hyperthyroidism in isolated rat aortae // Gen. Pharmacol. Vasc. Syst. 2000. Vol. 34. N 6. P. 429–434.
52. Deng J., Zhao R., Zhang Z., Wang J. Changes in vasoreactivity of rat large- and medium-sized arteries induced by hyperthyroidism // Exp. Toxicol. Pathol. 2010. Vol. 62. N 3. P. 317–322.
53. Гайнуллина Д.К., Селиванова Е.К., Шарова А.П., Тарасова О.С. Повышение констрикторного влияния Rho-киназы в артериях скелетных мышц и сердца при хроническом гипотиреозе у крыс // Бюлл. сиб. мед. 2018. Т. 17. № 4. С. 23–32.
54. Iwata T., Honda H. Acute hyperthyroidism alters adrenoceptor- and muscarinic receptor-mediated responses in isolated rat renal and femoral arteries // Eur. J. Pharmacol. 2004. Vol. 493. N 1–3. P. 191–199.
55. Zwaveling J., Pfaffendorf M., van Zwieten P.A. The direct effects of thyroid hormones on rat mesenteric resistance arteries // Fundam. Clin. Pharmacol. 1997. Vol. 11. N 1. P. 41–46.
56. Gaynullina D.K., Sofronova S.I., Selivanova E.K., Shvetsova A.A., Borzykh A.A., Sharova A.P., Kostyunina D.S., Martyanov A.A., Tarasova O.S. NO-mediated anticontractile effect of the endothelium is abolished in coronary arteries of adult rats with antenatal/early postnatal hypothyroidism // Nitric Oxide. 2017. Vol. 63. P. 21–28.
57. Luidens M.K., Mousa S.A., Davis F.B., Lin H.Y., Davis P.J. Thyroid hormone and angiogenesis // Vascul. Pharmacol. 2010. Vol. 52. N 3–4. P. 142–145.
58. Yoshida T., Gong J., Xu Z., Wei Y., Duh E.J. Inhibition of pathological retinal angiogenesis by the integrin αvβ3 antagonist tetraiodothyroacetic acid (tetrac) // Exp. Eye Res. 2012. Vol. 94. N 1. P. 41–48.
59. Mousa S.A., Bergh J.J., Dier E., Rebbaa A., O’Connor L.J., Yalcin M., Aljada A., Dyskin E., Davis F.B., Lin H., Davis P.J. Tetraiodothyroacetic acid, a small molecule integrin ligand, blocks angiogenesis induced by vascular endothelial growth factor and basic fibroblast growth factor // Angiogenesis. 2008. Vol. 11. N 2. P. 183–190.
60. Millard M., Odde S., Neamati N. Integrin targeted therapeutics // Theranostics. 2012. Vol. 1. P. 154–188.
61. Yoneda K., Takasu N., Higa S., Oshiro C., Oshiro Y., Shimabukuro M., Asahi T. Direct effects of thyroid hormones on rat coronary artery: nongenomic effects of triiodothyronine and thyroxine // Thyroid. 1998. Vol. 8. N 7. P. 609–613.
62. Barreto-Chaves M.L., De Souza Monteiro P., Fürstenau C.R. Acute actions of thyroid hormone on blood vessel biochemistry and physiology // Curr. Opin. Endocrinol. Diabetes Obes. 2011. Vol. 18. N 5. P. 300–303.
63. Lozano-Cuenca J., Lopez-Canales O.A., AguilarCarrasco J.C., Villagrana-Zesati J.R., Lopez-Mayorga R.M., Castillo-Henkel E.F., Lopez-Canales J.S. Pharmacological study of the mechanisms involved in the vasodilator effect produced by the acute application of triiodothyronine to rat aortic rings // Brazilian J. Med. Biol. Res. 2016. Vol. 49. N 8. P. 1–9.
64. Gachkar S., Nock S., Geissler C., Oelkrug R., Johann K., Resch J., Rahman A., Arner A., Kirchner H., Mittag J. Aortic effects of thyroid hormone in male mice // J. Mol. Endocrinol. 2019. Vol. 62. N 3. P. 91–99.
65. Colantuoni A., Marchiafava P.L., Lapi D., Forini F.S., Iervasi G. Effects of tetraiodothyronine and triiodothyronine on hamster cheek pouch microcirculation // Am. J. Physiol. Heart Circ. Physiol. 2005. Vol. 288. N 4. P. H1931–H1936.
66. Kimura K., Shirozaki Y., Jujo S., Shizuma T., Fukuyama N.. Nakazawa H. Triiodothyronine acutely increases blood flow in the ventricles and kidneys of anesthesized rabbits // Thyroid. 2006. Vol. 16. N 4. P. 357–360.
67. Krasner J.L., Wendling W.W., Cooper S.C., Chen D., Hellman S.K., Eldridge C.J., McClurken J.B., Jeevanandam V., Carlsson C. Direct effects of triiodothyronine on human internal mammary artery and saphenous veins // J. Cardiothorac. Vasc. Anesth. 1997. Vol. 11. N 4. P. 463–466.
68. Schmidt B.M.W., Martin N., Georgens A.C., Tillman H., Feuring M., Christ M., Wehling M. Nongenomic cardiovascular effects of triiodothyronine in euthyroid male volunteers // J. Clin. Endocrinol. Metab. 2002. Vol. 87. N 4. P. 1681–1686.
69. Cai Y., Manio M.M., Leung G.P.H., Xu A., Tang E.H.C., Vanhoutte P.M. Thyroid hormone affects both endothelial and vascular smooth muscle cells in rat arteries // Eur. J. Pharmacol. 2015. Vol. 747. P. 18–28.
70. Liu K.L., Lo M., Canaple L., Gauthier K., Carmine P., Beylot M. Vascular function of the mesenteric artery isolated from thyroid hormone receptor-α knockout mice // J. Vasc. Res. 2014. Vol. 51. N 5. P. 350–359.
71. Park K.W., Dai H.B., Ojamaa K., Lowenstein E., Klein I., Sellke F.W. The direct vasomotor effect of thyroid hormones on rat skeletal muscle resistance arteries // Anesth. Analg. 1997. Vol. 85. N 4. P. 734–738.
72. Selivanova E., Gaynullina D., Tarasova O. Endothelium and Rho-kinase are not essential for nongenomic relaxatory effects of thyroxine in rat skeletal muscle arteries // Acta Physiol. (Oxf.). 2019. Vol. 227. N S721. P. 119.
73. Carrillo-Sepulveda M.A., Ceravolo G.S., Fortes Z.B., Carvalho M.H., Tostes R.C., Laurindo F.R. Webb R.C., Barreto-Chaves M.L.M. Thyroid hormone stimulates NO production via activation of the PI3K/Akt pathway in vascular myocytes // Cardiovasc. Res. 2010. Vol. 85. N 3. P. 560–570.
74. Гайнуллина Д.К., Кирюхина О.О., Тарасова О.С. Оксид азота в эндотелии сосудов: регуляция продукции и механизмы действия // Усп. физиол. наук. 2013. Т. 44. № 4. С. 88–102.
75. Ojamaa K., Klemperer J.D., Klein I. Acute effects of thyroid hormone on vascular smooth muscle // Thyroid. 1996. Vol. 6. N 5. P. 505–512.
76. Flamant F., Samarut J. Thyroid hormone receptors: Lessons from knockout and knock-in mutant mice // Trends Endocrinol. Metab. 2003. Vol. 14. N 2. P. 85–90.
77. Aoki T., Tsunekawa K., Araki O., Ogiwara T., Nara M., Sumino H., Kimura T., Murakami M. Type 2 iodothyronine deiodinase activity is required for rapid stimulation of PI3K by thyroxine in human umbilical vein endothelial cells // Endocrinology. 2015. Vol. 156. N 11. P. 4312–4324.
Review
For citations:
Selivanova E.K., Tarasova O.S. Nongenomic effects of thyroid hormones: role in regulation of the vascular system. Vestnik Moskovskogo universiteta. Seriya 16. Biologiya. 2020;75(4):226-236. (In Russ.)
Views:
497
Email this article 