Abstract
In various models of cardiac hypertrophy, e.g. treatment of rats with norepinephrine infusion or pressure overload, increased expression of cytokines together with increase in extracellular matrix proteins (ECMP) was reported. In this study the effect of triiodothyronine (T3) on the expression of mRNA for cytokines and ECMP was investigated. Female Sprague-Dawley rats were treated daily with T3 in a dose of 0.2 mg.kg−1 of body weight s.c. Changes in the left (LV) and right (RV) ventricular function were measured 6, 24, 48, 72 h and 7 and 14 days after the first T3-injection using Millar ultraminiature pressure catheter transducers. RNA was isolated from LV and RV tissue, and the expression of cytokines and ECMP was measured using the ribonuclease protection assay. T3-treatment induced a significant increase in LV dP/dtmax and RV dP/dtmax, (p < 0.05) 24 h after the first injection of T3 together with an increase in heart rate (p < 0.01). The RV systolic pressure increased 48 h after the first T3 injection, whereas the LV systolic pressure remained unchanged. After 48 h the heart weight to body weight ratio was increased (p< 0.01). Hypertrophy of the RV was more prominent than that of the LV (155.9 vs. 137.7%).
In all groups the expression of mRNA for interleukins (IL) IL-6, IL-1β, IL-1α and tumour necrosis factor (TNF)-α in both ventricles did not change (p > 0.05). There was a significant increase in the mRNA for colligin 24 h after the T3 injection in both LV (p < 0.01) and RV (p< 0.05). This was followed by an increase in the mRNA for collagen I and III 72 h after the first T3-dose (p < 0.05 in RV; p < 0.01 in LV). At this point, the mRNA for tissue inhibitor of matrix metalloproteinases-2 (TIMP-2) was increased (p < 0.01) in the LV only. Moreover, after 7 days also the mRNA for matrix metalloproteinase (MMP)-2 increased (p < 0.01) in the LV. Both, TIMP-2 and MMP-2 were increased in the RV only after 14 days (p < 0.05). The gelatinase activity of MMP-2, however, was unchanged in both ventricles. The T3-induced cardiac hypertrophy was not accompanied by fibrosis as measured by the Sirius red staining after 14-days of T3-treatment. The moderate increase in mRNA for ECMP and MMP may be attributed more to the increasing mass of the ventricles with the accompanying remodelling of the ECM than to increased fibrosis.
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Boluyt MO, O'Neill L, Meredith AL, Bing OHL, Brooks WW, Conrad ChH, Crow MT, Lakatta EG: Alterations in cardiac gene expression during transition from stable hypertrophy to heart failure. Marked upregulation of genes encoding extracellular matrix components. Circ Res 75: 23-32, 1994
Weber KT, Sun Y, Tyagi SC, Cleutjens JP: Collagen network of the myocardium: Function, structural remodelling and regulatory mechanisms. J Mol Cell Cardiol 26: 279-292, 1994
Li YY, McTierman ChF, Fieldman AM: Interplay of matrix metalloproteinases, tissue inhibitors of metalloproteinases and their regulators in cardiac matrix remodelling. Cardiovasc Res 46: 214-224, 2000
Hirota H, Yoshida K, Kishimoto T, Taga T: Continuous activation of gp130, a signal-transducing receptor component for interleukin 6-related cytokines, causes myocardial hypertrophy in mice. Proc Natl Acad Sci USA 92: 4862-4866, 1995
Amento EP, Ehsani N, Palmer H, Libby P: Cytokines and growth factors positively and negatively regulate interstitial collagen gene expression in human vascular smooth muscle cells. Arterioscler Thromb 11: 1223-1230, 1991
Li YY, McTierman ChF, Fieldman AM: Proinflamatory cytokines regulate tissue inhibitors of metalloproteinases and disintegrin metalloproteinase in cardiac cells. Cardiovasc Res 42: 162-172, 1999
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 89: 591-598, 2001
Zimmer HG, Irlbeck M, Kolbeck-Rühmkorff C: Response of the rat heart to catecholamines and thyroid hormones. Mol Cell Biochem 147: 105-114, 1995
Lee HJ, Yen PM: Recent advances in understanding thyroid hormone receptor coregulators. J Biomed Sci 6: 71-78, 1999
Wu Y, Koenig RJ: Gene regulation by thyroid hormone. Trends Endocrinol Metab 11: 207-211, 2000
Zierhut W, Zimmer HG: Differential effects of triiodothyronine on rat left and right ventricular function and the influence of metoprolol. J Mol Cell Cardiol 21: 617-624, 1989
Briest W, Hölzl A, Raßler B, Deten A, Leicht M, Baba HA, Zimmer HG: Cardiac remodelling after long term norepinephrine treatment in rats. Cardiovasc Res 52: 265-273, 2001
Tyagi SC, Matsubara L, Weber KT: Direct extraction and estimation of collagenase(s) activity by zymography in microquantities of rat myocardium and uterus. Clin Biochem 64: 133-148, 1979
Baba HA, Takaaki I, Bauer M, Irlbeck M, Schmid KW, Zimmer HG: Differential effects of angiotensin II receptor blockade on pressure-induced left ventricular hypertrophy and fibrosis in rats. J Mol Cell Cardiol 31: 445-455, 1999
Lomax RB, Cobbold PH, Allshire AP, Cuthbertson KS, Robertson WR: Tri-iodothyronine increases intracellular calcium levels in single rat myocytes. J Mol Endocrinol 7: 77-79, 1991
Gotzsche LB: L-triiodothyronine acutely increases Ca2+ uptake in the isolated, perfused rat heart. Changes in L-type Ca2+ channels and beta-receptors during short-and long-term hyper-and hypothyroidism. Eur J Endocrinol 130: 171-179, 1994
Sun ZQ, Ojamaa K, Nakamura TY, Artman M, Klein I, Coetzee WA: Thyroid hormone increases pacemaker activity in rat neonatal atrial myocytes. J Mol Cell Cardiol 33: 811-824, 2001
Atkins FL, Carney R, Love S: Regression of thyroid hormone induced cardiac hypertrophy: Effect on cardiac beta receptors and adenyl cyclase activity. Life Sci 33: 679-685, 1983
Hammond HK, White FC, Boxton H, Salzstein P, Brunton LL, Longhurst JC: Increased myocardial beta-receptors and adrenergic responses in hyperthyroid pigs. Am J Physiol 252: H283-H290, 1987
Bahouth SW, Cui X, Beauchamp MJ, Park EA: Thyroid hormone induces beta1-adrenergic receptor gene transcription through a direct repeat separated by five nucleotides. J Mol Cell Cardiol 29: 3223-3237, 1997
Zimmer HG, Heckmann M, Lortet S: Cardiovascular response to triiodothyronine in Sprague-Dawley and spontaneously hypertensive rats. Cardioscience 4: 157-162, 1993
Clarke EP, Jain N, Brickenden A, Lorimer IA, Sanwal BD: Parallel regulation of procollagen I and colligin, a collagen-b protein and a member of the serine protease inhibitor family. J Cell Biol 121: 193-199, 1993
Dolgilevich SM, Siri FM, Atlas SA, Eng C: Changes in collagenase and collagen gene expression after induction of aortocaval fistula in rats. Am J Physiol 281: H207-H214, 2001
Susin M, Herdson PB: Fine structural changes in rat myocardium induced by thyroxine and by magnesium deficiency. Arch Pathol 83: 86-98, 1967
Gerdes AM, Moore JA, Bishop SP: Failure of propranolol to prevent chronic hyperthyroid induced cardiac hypertrophy and multifocal cellular necrosis in the rat. Can J Cardiol 1: 340-345, 1985
Yao J, Eghbali M: Decreased collagen gene expression and absence of fibrosis in thyroid hormone-induced myocardial hypertrophy. Response of cardiac fibroblasts to thyroid hormone in vitro. Circ Res 71: 831-839, 1992
Klein LE, Sigel AV, Douglas JA, Eghbali-Webb M: Upregulation of collagen type I gene expression in the ventricular myocardium of thyroidectomized male and female rats. J Mol Cell Cardiol 28: 33-42, 1996
Barth W, Deten A, Bauer M, Reinohs M, Leicht M, Zimmer HG: Differential remodelling of the left and right heart after norepinephrine treatment in rats: Studies on cytokines and collagen. J Mol Cell Cardiol 32: 273-284, 2000
Lijnen PJ, Petrov VV, Fagard RH: Induction of cardiac fibrosis by transforming growth factor-beta 1. Mol Genet Metab 71: 418-435, 2000
Deten A, Hölzl A, Leicht M, Barth W, Zimmer HG: Changes in extracellular matrix and in transforming growth factor beta isoforms after coronary artery ligation in rats. J Mol Cell Cardiol 33: 1191-1207, 2001
Kunisada K, Hirota H, Fujio Y, Matsui H, Tani Y, Yamauchi-Takihara K, Kishimoto T: Activation of JAK-STAT and MAP kinases by leukemia inhibitory factor through gp130 in cardiac myocytes. Circulation 94: 2626-2632, 1996
Pan J, Fukuda K, Saito M, Matsuzaki J, Kodama H, Sano M, Takahashi T, Kato T, Ogawa S: Mechanical stretch activates the JAK/STAT pathway in rat cardiomyocytes. Circ Res 84: 1127-1136, 1999
Katz D, Lazar MA: Dominant negative activity of an endogenous thyroid hormone receptor variant (alpha 2) is due to competition for binding sites on target genes. J Biol Chem 268: 20904-20910, 1993
Umesono K, Giguere V, Glass CK, Rosenfeld MG, Evans RM: Retinoic acid and thyroid hormone induce gene expression through a common responsive element. Nature 336: 262-265, 1988
Meier-Heusler SC, Zhu X, Juge-Aubry C, Pernin A, Burger AG, Chong SY, Meier CA: Modulation of thyroid hormone action by mutant thyroid hormone receptors, c-erbA alpha 2 and peroxisome proliferator-activated receptor: Evidence for different mechanisms of inhibition. Mol Cell Endocrinol 107: 55-66, 1995
McInerney EM, Rose DW, Flynn SE, Westin S, Mullen TM, Krones A, Inostroza J, Torchia J, Nolte RT, Assa-Munt N, Milburn MV, Glass ChK, Rosenfeld MG: Determinants of coactivator LXXLL motif specificity in nuclear receptor transcriptional activation. Genes Dev 12: 3357-3368, 1999
Carter WJ, Kelly WF, Fass FH, Lynch ME, Perry CA: Effect of graded doses of tri-iodothyronine on ventricular myosin ATPase activity and isomyosin profile in young and old rats. Biochem J 247: 329-334, 1987
Long X, Boluyt MO, O'Neill L, Zheng JS, Wu G, Nitta YK, Crow MT, Lakatta EG: Myocardial retinoid X receptor, thyroid hormone receptor, and myosin heavy chain gene expression in the rat during adult aging. J Genotol A Biol Sci Med Sci 54: B23-B27, 1999
Sugawara A, Yen PM, Apriletti JW, Ribeiro RC, Sacks DB, Baxter JD, Chin WW: Phosphorylation selectively increases triiodothyronine receptor homodimer binding to DNA. J Biol Chem 269: 433-437, 1994
Yamamoto N, Li QL, Mita S, Morisawa S, Inoue A: Inhibition of thyroid hormone binding to the nuclear receptor by mobilization of free fatty acids. Horm Metab Res 33: 131-137, 2001
Becker N, Seugnet I, Guissouma H, Dupre SM, Demeneix BA: Nuclear corepressor and silencing mediator of retinoic acid and thyroid hormone receptors corepressor is incompatible with T(3)-dependent TRH regulation. Endocrinology 142: 5321-5331, 2001
Schaub MC, Hefti MA, Harder BA, Eppenberger HM: Various hypertrophic stimuli induce distinct phenotypes in cardiomyocytes. J Mol Med 75: 901-920, 1997
Schmidt ED, Cramer SJ, Offringa R: The thyroid hormone receptor interferes with transcriptional activation via the AP-1 complex. Biochem Biophys Res Commun 192: 151-160, 1993
Chen WJ, Lin KH, Lee YS: Molecular characterization of myocardial fibrosis during hypothyroidism: Evidence for negative regulation of the pro-alpha1(I) collagen gene expression by thyroid hormone receptor. Mol Cell Endocrinol 162: 45-55, 2000
Lee HW, Klein LE, Raser J, Eghbali-Webb M: An activator protein-1 (AP-1) response element on pro alpha1(l) collagen gene is necessary for thyroid hormone-induced inhibition of promoter activity in cardiac fibroblasts. J Mol Cell Cardiol 30: 2495-2506, 1998
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Ziegelhöffer-Mihalovičová, B., Briest, W., Baba, H.A. et al. The expression of mRNA of cytokines and of extracellular matrix proteins in triiodothyronine-treated rat hearts. Mol Cell Biochem 247, 61–68 (2003). https://doi.org/10.1023/A:1024153003249
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DOI: https://doi.org/10.1023/A:1024153003249