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Modification of cardiac thyroid hormone deiodinases expression in an ischemia/reperfusion rat model after T3 infusion

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Abstract

The deiodinases regulate the activation and inactivation of Thyroid hormones (TH), in both physiological and pathological conditions. The three deiodinases, DIO1, DIO2 and DIO3, have different catalytic role and cellular and tissue distribution. Aim of this study is to evaluate a rat model of regional ischemia/reperfusion (I/R), the modification of cardiac main function after the administration of 6 µg/kg/day of triiodothyronine (T3), and the associated to DIO1, DIO2 and DIO3 gene expression. We also aim to study DIO1 and DIO2 protein levels in different left ventricular regions after an ischemic event. Four groups of rats were studied: sham-operated, sham-operated + T3, I/R rats and I/R rats + T3. DIO1, DIO2 and DIO3 expression were evaluated in I/R region (AAR: area-at-risk) and in a more distant region from ischemic wound (RZ: remote zone). In I/R group, circulating free-T3 (FT3) levels were significantly decreased with respect to basal values, whereas in I/R + T3 rats, FT3 levels were comparable to basal values. In AAR of I/R + T3 rats, DIO1 and DIO2 gene expression significantly increased with respect to sham. In RZ, DIO1 and DIO3 gene expression was significantly lower in sham and I/R rats when compared to I/R + T3. In sham + T3 group, DIO1 and DIO2 gene expression was not detectable, whereas DIO3 was significantly higher than in the other three groups. The present study gives interesting new insights on DIO1, DIO2 and DIO3 in the ischemic heart and their role in relation to T3-mediated amelioration of cardiac function and structure.

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References

  1. Pantos CI, Malliopoulou VA, Mourouzis IS, Karamanoli EP, Paizis IA, Steimberg N, Varonos DD, Cokkinos DV (2004) Long-term thyroxine administration protects the heart in a pattern similar to ischemic preconditioning. Thyroid. https://doi.org/10.1089/10507250252949469

    Article  Google Scholar 

  2. Lee S, Farwell AP (2016) Euthyroid sick syndrome. Compr Physiol 6:1071–1080. https://doi.org/10.1002/cphy.c150017

    Article  PubMed  Google Scholar 

  3. Sato Y, Yoshihisa A, Kimishima Y, Kiko T, Kanno Y, Yokokawa T, Abe S, Misaka T, Sato T, Oikawa M, Kobayashi A, Yamaki T, Kunii H, Nakazato K, Takeishi Y (2019) Low T3 syndrome is associated with high mortality in hospitalized patients with heart failure. J Card Fail 25:195–203. https://doi.org/10.1016/j.cardfail.2019.01.007

    Article  PubMed  Google Scholar 

  4. Pingitore A, Landi P, Taddei MC, Ripoli A, L'Abbate A, Iervasi G (2005) Triiodothyronine levels for risk stratification of patients with chronic heart failure. Am J Med 118:132–136. https://doi.org/10.1016/j.amjmed.2004.07.052

    Article  CAS  PubMed  Google Scholar 

  5. Rothberger GD, Gadhvi S, Michelakis N, Kumar A, Calixte R, Shapiro LE (2017) Usefulness of serum triiodothyronine (T3) to predict outcomes in patients hospitalized with acute heart failure. Am J Cardiol 119:599–603. https://doi.org/10.1016/j.amjcard.2016.10.045

    Article  CAS  PubMed  Google Scholar 

  6. Gereben B, Zavacki AM, Ribich S, Kim BW, Huang SA, Simonides WS, Zeöld A, Bianco AC (2008) Cellular and molecular basis of deiodinase-regulated thyroid hormone signaling. Endocr Rev 29:898–938. https://doi.org/10.1210/er.2008-0019

    Article  CAS  PubMed  Google Scholar 

  7. Bianco AC, Salvatore D, Gereben B, Berry MJ, Larsen PR (2002) Biochemistry, cellular and molecular biology, and physiological roles of the iodothyronine selenodeiodinases. Endocr Rev 23:38–89. https://doi.org/10.1210/edrv.23.1.0455

    Article  CAS  PubMed  Google Scholar 

  8. Toyoda N, Kaptein E, Berry MJ, Harney JW, Larsen PR, Visser TJ (1997) Structure–activity relationships for thyroid hormone deiodination by mammalian type i iodothyronine deiodinases. Endocrinology 138:213–219. https://doi.org/10.1210/endo.138.1.4900

    Article  CAS  PubMed  Google Scholar 

  9. Oppenheimer JH, Schwartz HL, Surks MI (1972) Propylthiouracil inhibits the conversion of L-thyroxine to L-triiodothyronine: an explanation of the antithyroxine effect of propylthiouracil and evidence supporting the concept that triiodothyronine is the active thyroid hormone. J Clin Invest 51:2493–2497. https://doi.org/10.1172/JCI107063

    Article  CAS  PubMed  Google Scholar 

  10. Olivares EL, Marassi MP, Fortunato RS, da Silva ACM, Costa-e-Sousa RH, Araújo IG, Mattos EC, Masuda MO, Mulcahey MA, Huang SA, Bianco AC, Carvalho DP (2007) Thyroid function disturbance and type 3 iodothyronine deiodinase induction after myocardial infarction in Rats-A time course study. Endocrinology 148:4786–4792. https://doi.org/10.1210/en.2007-0043

    Article  CAS  PubMed  Google Scholar 

  11. Pol CJ, Muller A, Simonides WS (2010) Cardiomyocyte-specific inactivation of thyroid hormone in pathologic ventricular hypertrophy: an adaptative response or part of the problem? Heart Fail Rev 15:133–142. https://doi.org/10.1007/s10741-008-9133-7

    Article  CAS  PubMed  Google Scholar 

  12. Pol CJ, Muller A, Zuidwijk MJ, van Deel ED, Kaptein E, Saba A, Marchini M, Zucchi R, Visser TJ, Paulus WJ, Duncker DJ, Simonides WS (2011) Left-ventricular remodeling after myocardial infarction is associated with a cardiomyocyte-specific hypothyroid condition. Endocrinology 152:669–679. https://doi.org/10.1210/en.2010-0431

    Article  CAS  PubMed  Google Scholar 

  13. Boelen A, Maas MA, Lowik CW, Platvoet MC, Wiersinga MW (1996) Induced illness in interleukin-6 (IL-6) knock-out mice: a causal role of IL-6 in the development of the low 3,5,3'-triiodothyronine syndrome. Endocrinology 137:5250–5254. https://doi.org/10.1210/endo.137.12.8940342

    Article  CAS  PubMed  Google Scholar 

  14. Simonides WS, Mulcahey MA, Redout EM, Muller A, Zuidwijk MJ, Visser TJ, Wassen FW, Crescenzi A, da-Silva WS, Harney J, Engel FB, Obregon M-J, Larsen PR, Bianco AC, Huang SA (2008) Hypoxia inducible factor induces local thyroid hormone inactivation during hypoxic-ischemic disease in rats. J Clin Invest 118:975–983. https://doi.org/10.1172/JCI32824

    Article  CAS  PubMed  Google Scholar 

  15. Dentice M, Morisco C, Vitale M, Rossi G, Fenzi G, Salvatore D (2003) The different cardiac expression of the type 2 iodothyronine deiodinase gene between human and rat is related to the differential response of the Dio2 genes to Nkx-2.5 and GATA-4 transcription factors. Mol Endocrinol 17:1508–1521. https://doi.org/10.1210/me.2002-0348

    Article  CAS  PubMed  Google Scholar 

  16. Sabatino L, Iervasi G, Ferrazzi P, Francesconi D, Chopra IJ (2000) A study of iodothyronine 5′-monodeiodinase activities in normal and pathological tissues in man and their comparison with activities in rat tissues. Life Sci 68:191–202. https://doi.org/10.1016/s0024-3205(00)00929-2

    Article  CAS  PubMed  Google Scholar 

  17. Sabatino L, Chopra IJ, Tanavoli S, Iacconi P, Iervasi G (2001) A radioimmunoassay for type I iodothyronine 5′-monodeiodinase in human tissues. Thyroid 11:733–739. https://doi.org/10.1089/10507250152484565

    Article  CAS  Google Scholar 

  18. Sabatino L, Balzan S, Kusmic C, Iervasi G (2018) Modification of gene expression profiling related to renin-angiotensin system in an ischemia/reperfusion rat model after T3 infusion. Mol Cell Biochem 449:277–283. https://doi.org/10.1007/s11010-018-3364-2

    Article  CAS  Google Scholar 

  19. Saba A, Donzelli R, Colligiani D, Raffaelli A, Nannipieri M, Kusmic C, Dos Remedios CG, Simonides WS, Iervasi G, Zucchi R (2014) Quantification of thyroxine and 3,5,3′-triiodo-thyronine in human and animal hearts by a novel liquid chromatography-tandem mass spectrometry method. Horm Metab Res 46:628–634. https://doi.org/10.1055/s-0034-1368717

    Article  CAS  PubMed  Google Scholar 

  20. Ojamaa K, Kenessey A, Shenoy R, Klein I (2000) Thyroid hormone metabolism and cardiac gene expression after acute myocardial infarction in the rat. Am J Physiol Endocrinol Metab 279:E1319–E1324. https://doi.org/10.1152/ajpendo.2000.279.6.E1319

    Article  CAS  PubMed  Google Scholar 

  21. Bianco AC, da Conceição RR (2018) The deiodinase trio and thyroid hormone signaling. Methods Mol Biol 1801:67–83. https://doi.org/10.1007/978-1-4939-7902-8_8

    Article  CAS  PubMed  Google Scholar 

  22. Luongo C, Dentice M, Salvatore D (2019) Deiodinases and their intricate role in thyroid hormone homeostasis. Nat Rev Endocrinol 15:479–488. https://doi.org/10.1038/s41574-019-0218-2

    Article  PubMed  Google Scholar 

  23. Baqui MM, Gereben B, Harney JW, Larsen PR, Bianco AC (2000) Distinct subcellular localization of transiently expressed types 1 and 2 iodothyronine deiodinases as determined by immunofluorescence confocal microscopy. Endocrinology 141:4309–4312. https://doi.org/10.1210/endo.141.11.7872

    Article  CAS  PubMed  Google Scholar 

  24. Maia AL, Goemann IM, Meyer EL, Wajner SM (2011) Type 1 iodothyronine deiodinase in human physiology and disease. J Endocrinol 209:283–297. https://doi.org/10.1530/JOE-10-0481

    Article  CAS  PubMed  Google Scholar 

  25. Rajagopalan V, Zhang Y, Ojamaa K, Ojamaa K, Chen Y-F, Pingitore A, Pol CJ, Saunders D, Balasubramanian K, Towner RA, Gerdes AM (2016) Safe oral triiodo-L-thyronine therapy protects from post-infarct cardiac dysfunction and arrhythmias without cardiovascular adverse effects. PLoS ONE 11:e0151413. https://doi.org/10.1371/journal.pone.0151413

    Article  CAS  PubMed  Google Scholar 

  26. Gereben B, Goncalves C, Harney JW, Larsen PR, Bianco AC (2000) Selective proteolysis of human type 2 deiodinase: a novel ubiquitin-proteasomal mediated mechanism for regulation of hormone activation. Mol Endocrinol 14:1697–1708. https://doi.org/10.1210/mend.14.11.0558

    Article  CAS  PubMed  Google Scholar 

  27. Steinsapir J, Bianco AC, Buettner C, Harney J, Larsen PR (2000) Substrate-induced down-regulation of human type 2 deiodinase (hD2) is mediated through proteasomal degradation and requires interaction with the enzyme's active center. Endocrinology 141:1127–1135. https://doi.org/10.1210/endo.141.3.7355

    Article  CAS  PubMed  Google Scholar 

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Acknowledgements

The authors want to thank Dr.Sohrab Tanavoli for helpful English revision and Dr. Silvana Balzan for useful advice.

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  1. Institute of Clinical Physiology, National Research Council (C.N.R.), Pisa, Italy

    Laura Sabatino, Claudia Kusmic & Giorgio Iervasi

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  1. Laura Sabatino
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Correspondence to Laura Sabatino.

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Sabatino, L., Kusmic, C. & Iervasi, G. Modification of cardiac thyroid hormone deiodinases expression in an ischemia/reperfusion rat model after T3 infusion. Mol Cell Biochem 475, 205–214 (2020). https://doi.org/10.1007/s11010-020-03873-w

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