Hypothyroidism and Oxidative Stress: Differential Effect on the Heart of Virgin and Pregnant Rats

Abstract

The present study investigates the effects of hypothyroidism on both the redox state and the thyroid hormone receptors expression in the heart ventricle of virgin and pregnant rats.

Hypothyroid state was induced by 6-n-propyl-2-thiouracil in drinking water given to Wistar rats starting 8 days before mating until day 21 of pregnancy or for 30 days in virgin rats. Serum paraoxonase-1 (PON-1) activity, serum and heart nitrites, and thiobarbituric acid-reactive substances (TBARS) were analyzed. Heart protein oxidation, as carbonyls, and copper-zinc superoxide dismutase (CuZnSOD), glutathione peroxidase (GPx), and catalase (CAT) activities, were determined. In addition, heart expressions of NADPH oxidase (NOX-2), CAT, SOD, GPx, and thyroid receptors (TRα and TRβ) mRNA were assessed by RT-PCR. Inducible and endothelial Nitric Oxide Synthase (iNOS and eNOS) were determined by Western blot. Hypothyroidism in the heart of virgin rats decreased TRα and TRβ expressions, and induced oxidative stress, leading to a decrease of nitrites and an increase of carbonyls, NOX-2 mRNA, and GPx activity. A decreased PON-1 activity suggested low protection against oxidative stress in blood circulation. Pregnancy reduced TRα and TRβ mRNA expressions and induced oxidative stress by increasing nitrite and TBARS levels, SOD and CAT activities and NOX-2, eNOS and iNOS expressions, while hypothyroidism, emphasized the decreases of TRα mRNA levels and did not alter the redox state in the heart. TR expressions and redox balance of rat hearts depend on the physiological state. Pregnancy per se seems to protect the heart against oxidative stress induced by hypothyroidism.

Supporting Information for this article is available online at http://www.thieme-connect.de/ejournals/toc/hmr

Key words

thyroid hormone - thyroid hormone receptor - redox state - myocardium

^* Member of CONICET (National Investigations Council of Science and Technology), Argentina.

• References

• 1 Fazio S, Palmieri EA, Lombardi G, Biondi B. Effects of thyroid hormone on the cardiovascular system. Recent Prog Horm Res 2004; 59: 31-50
• 2 Weiss RE, Korcarz C, Chassande O, Cua K, Sadow PM, Koo E, Samarut J, Lang R. Thyroid hormone and cardiac function in mice deficient in thyroid hormone receptor α or β: an echocardiograph study. Am J Physiol Endocrinol Metab 2002; 283: 428-435
• 3 Gloss B, Trost SU, Bluhm WF, Swanson EA, Clarck R, Winkfein R, Jansen KM, Giles W, Chassande O, Samarut J, Dillman WH. Cardiac ion channel expression and contractile function in mice with deletion of thyroid hormone receptor α or β. Endocrinology 2001; 142: 544-550
• 4 Liu CR, Li LY, Shi F, Zang XY, Liu YM, Sun Y, Kan BH. Effects of hyper- and hypothyroid on expression of thyroid hormone receptor mRNA in rat myocardium. J Endocrinol 2007; 195: 429-438
• 5 Mishra P, Samanta L. Oxidative stress and heart failure in altered thyroid state. Scientific World Journal [Internet] 2012 Available from: http://www.hindawi.com/journals/tswj/2012/741861/abs/
• 6 Venditti P, Balestrieri M, Di Mateo S, De Leo T. Effect of thyroid state on lipid peroxidation, antioxidant defences and susceptibility to oxidative stress in rat tissue. J Endocrinol 1997; 155: 151-157
• 7 Gredilla R, Barja G, López-Torres M. Thyroid hormone-induced oxidative damage on lipids, glutathione and DNA in the mouse heart. Free Radic Res 2001; 35: 417-425
• 8 Mogulkoc R, Baltaci AK, Aydin L, Oztekin E, Sivrikaya A. The effect of thyroxine administration on lipid peroxidation in different tissues of rats with hypothyroidism. Acta Physiol Hung 2005; 92: 39-46
• 9 Griendling KK, Sorescu D, Ushio-Fukai M. NAD(P)H oxidase: role in cardiovascular biology and disease. Circ Res 2000; 86: 494-501
• 10 Takimoto E, Kass DA. Role of oxidative stress in cardiac hypertrophy and remodelling. Hypertension 2007; 49: 241-248
• 11 Quesada A, Sainz J, Wangensteen R, Rodriguez-Gomez I, Vargas F, Osuna A. Nitric oxide synthase activity in hyperthyroid and hypothyroid rats. Eur J Endocrinol 2002; 147: 117-122
• 12 Sies H. Oxidative stress: oxidants and antioxidants. Exp Physiol 1997; 82: 291-295
• 13 Yilmaz S, Ozan S, Benzer F, Canatan H. Oxidative damage and antioxidant enzymes activities in experimental hypothyroidism. Cell Biochem Funct 2003; 21: 325-330
• 14 Messarah M, Boulakoud MS, Boumendjel A, Abdennour C, El Feki A. The impact of thyroid activity variations on some oxidizing-stress parameters in rats. C R Biol 2007; 330: 107-112
• 15 Sarandöl E, Taş S, Dirican M, Serdar Z. Oxidative stress and serum paraoxonase activity in experimental hypothyroidism: effect of vitamin E supplementation. Cell Biochem Funct 2005; 23: 1-8
• 16 Mackness B, Durrington PN, Mackness MI. Human serum paraoxonase. Gen Pharmacol 1998; 37: 329-336
• 17 Dorn II GW. The fuzzy logic of physiological cardiac hypertrophy. Hypertension 2007; 49: 962-970
• 18 Vannucchi CI, Jordao AA, Vannucchi H. Antioxidant compounds and oxidative stress in female dogs during pregnancy. Res Vet Sci 2007; 83: 188-193
• 19 Ohkawa H, Ohishi N, Yagi K. Assay for lipid peroxides in animal tissues by thiobarbituric acid reaction. Anal Biochem 1979; 95: 351-358
• 20 Gornall AG, Bardawill CJ, David MM. Determination of serum proteins by means of the biuret reaction. J BiolChem 1949; 177: 751-766
• 21 Beltowski J, Wojcicka G, Mydlarczyk M, Jamroz A. Cerivastatin modulates plasma paraoxonase/arylesterase activity and oxidant-antioxidant balance in the rat. Pol J Pharmacol 2002; 54: 143-150
• 22 Dalle-Donne I, Rossi R, Giustarini D, Milzani A, Colombo R. Protein carbonyl groups as biomarkers of oxidative stress. Clin Chim Acta 2003; 329: 23-38
• 23 Moshage H, Kok B, Huizenga JR, Jansen PL. Nitrite and nitrate determinations in plasma: A critical evaluation. Clin Chem 1995; 41: 892-896
• 24 Aebi H. Catalase in Vitro. Methods Enzymol 1984; 105: 121-126
• 25 Flohé L, Günzler WA. Assays of glutathione peroxidase. Methods Enzymol 1984; 105: 114-121
• 26 McCord JM, Fridovich I. Superoxide dismutase an enzymatic function for erythrocuprein. J Biol Chem 1969; 244: 49-55
• 27 Pasupathi P, Manivannan U, Manivannan P, Deepa M. Cardiac troponins and oxidative stress in non-pregnant, pregnant, and preeclampsia women. Bangladesh Med Res Counc Bull 2010; 36: 4-9
• 28 Pinto RE, Bartley W. The nature of sex-linked differences in glutathione peroxidase activity and aerobic oxidation of glutathione in male and female rat liver. Biochem J 1969; 115: 449-456
• 29 Osborne LJ, Tonissen KF, Tang VH, Clarke FM. Expression and localization of thioredoxin in mouse reproductive tissues during the oestrous cycle. Mol Reprod Dev 2001; 58: 359-367
• 30 Mooradian AD. Antioxidant properties of steroids. J Steriod Biochem Mol Biol 1993; 45: 509-511
• 31 Seiva FR, Ebaid GM, Castro AV, Okoshi K, Nascimento A, Rocha KK, Padovani CR, Cicogna AC, Novelli EL. Growth hormone and heart failure: Oxidative stress and energetic metabolism in rats. Growth Horm IGF Res 2008; 18: 275-283
• 32 Hapon MB, Simoncini M, Via G, Jahn GA. Effect of hypothyroidism on hormone profiles in virgin, pregnant and lactating rats, and on lactation. Reproduction 2003; 126: 371-382
• 33 Kinugawa K, Yonekura K, Ribeiro RC, Eto Y, Aoyagi T, Baxter JD, Camacho SA, Bristow MR, Long CS, Simpson PC. Regulation of thyroid hormone receptor isoforms in physiological and pathological cardiac hypertrophy. Circ Res 2001; 89: 591-598
• 34 Makino A, Wang H, Scott BT, Yuan JX, Dillman WH. Thyroid hormone receptor-α and vascular function. Am J Physiol Cell Physiol 2012; 302: 1346-1352
• 35 Coria MJ, Carmona Viglianco YV, Marra CA, Gomez-Mejiba SE, Ramirez DC, Anzulovich AC, Gimenez MS. Hypothyroidism modifies lipid composition of polymorphonuclear leukocytes. Cell Physiol Biochem 2012; 29: 713-714
• 36 Ahmed OM, Gabar MA, Ali TM. Impacts of the coexistence of diabetes and hypothyroidism on body weight gain, leptin and various metabolic aspects in albino rats. J Diabetes Complications 2012; 26: 463-564
• 37 White RE, Gerrity R, Barman SA, Han G. Estrogen and oxidative stress: A novel mechanism that may increase the risk for cardiovascular disease in women. Steroids 2010; 75: 788-793
• 38 Zhang Y, Kaufman S. Effect of oxide nitric synthase inhibition on cardiovascular and hormonal regulation during pregnancy in rat. Can J Physiol Pharmacol 2000; 78: 423-427
• 39 Santos GM, Afonso V, Barra GB, Togashi M, Webb P, Neves FA, Lomri N, Lomri A. Negative regulation of superoxide dismutase-1 promoter by thyroid hormone. Mol Pharmacol 2006; 70: 793-800