Abstract
Although most of effects of Angiotensin II (Ang II) related to cardiac remodelling can be attributed to type 1 Ang II receptor (AT1R), the type 2 receptor (AT2R) has been shown to be involved in the development of some cardiac hypertrophy models. In the present study, we investigated whether the thyroid hormone (TH) action leading to cardiac hypertrophy is also mediated by increased Ang II levels or by change on AT1R and AT2R expression, which could contribute to this effect. In addition, we also evaluated the possible contribution of AT2R in the activation of Akt and in the development of TH-induced cardiac hypertrophy. To address these questions, Wistar rats were treated with thyroxine (T4, 0.1 mg/kg BW/day, i.p.), with or without AT2R blocker (PD123319), for 14 days. Cardiac hypertrophy was identified based on heart/body weight ratio and confirmed by analysis of atrial natriuretic factor mRNA expression. Cardiomyocyte cultures were used to exclude the influence of TH-related hemodynamic effects. Our results demonstrate that the cardiac Ang II levels were significantly increased (80%, P < 0.001) as well as the AT2R expression (50%, P < 0.05) in TH-induced cardiac hypertrophy. The critical involvement of AT2R to the development of this cardiac hypertrophy in vivo was evidenced after administration of AT2 blocker, which was able to prevent in 40% (P < 0.01) the cardiac mass gain and the Akt activation induced by TH. The role of AT2R to the TH-induced cardiomyocyte hypertrophy was also confirmed after using PD123319 in the in vitro studies. These findings improve understanding of the cardiac hypertrophy observed in hyperthyroidism and provide new insights into the generation of future therapeutic strategies.
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Barreto-Chaves ML, Heimann A, Krieger JE (2000) Stimulatory effect of dexamethasone on angiotensin-converting enzyme in neonatal rat cardiac myocytes. Braz J Med Biol Res 33:661–664
Berry C, Touyz R, Dominiczak AF, Webb RC, Johns DG (2001) Angiotensin receptors: signaling, vascular pathophysiology, and interactions with ceramide. Am J Physiol Heart Circ Physiol 281:H2337–H2365
Billet S, Aguilar F, Baudry C, Clauser E (2008) Role of angiotensin II AT1 receptor activation in cardiovascular diseases. Kidney Int 74:1379–1384
Booz GW (2004) Cardiac angiotensin AT2 receptor: what exactly does it do? Hypertension 43:1162–1163
Bradford MM (1976) A rapid and sensitive method for the quantitation of microgram quantities of protein utilizing the principle of protein–dye binding. Anal Biochem 72:248–254
Brent GA, Williams GR, Harney JW, Forman BM, Samuels HH, Moore DD, Larsen PR (1991) Effects of varying the position of thyroid hormone response elements within the rat growth hormone promoter: implications for positive and negative regulation by 3,5,3′-triiodothyronine. Mol Endocrinol 5:542–548
Burrow GN (1994) Thyroid dysfunction in the recently pregnant: postpartum thyroiditis. Thyroid 4:363–365
Carneiro-Ramos MS, da Silva VB, Coutinho MB Jr, Battastini AM, Sarkis JJ, Barreto-Chaves ML (2004) Thyroid hormone stimulates 5′-ecto-nucleotidase of neonatal rat ventricular myocytes. Mol Cell Biochem 265:195–201
Carneiro-Ramos MS, Diniz GP, Almeida J, Vieira RL, Pinheiro SV, Santos RA, Barreto-Chaves ML (2007) Cardiac angiotensin II type I and type II receptors are increased in rats submitted to experimental hypothyroidism. J Physiol 583:213–223
Carneiro-Ramos MS, Silva VB, Santos RA, Barreto-Chaves ML (2006) Tissue-specific modulation of angiotensin-converting enzyme (ACE) in hyperthyroidism. Peptides 11:2942–2949
Caruso-Neves C, Kwon SH, Guggino WB (2005) Albumin endocytosis in proximal tubule cells is modulated by angiotensin II through an AT2 receptor-mediated protein kinase B activation. Proc Natl Acad Sci USA 102:17513–17518
D’Amore A, Black MJ, Thomas WG (2005) The angiotensin II type 2 receptor causes constitutive growth of cardiomyocytes and does not antagonize angiotensin II type 1 receptor-mediated hypertrophy. Hypertension 46:1347–1354
de Gasparo M, Catt KJ, Inagami T, Wright JW, Unger T (2000) International union of pharmacology. XXIII. The angiotensin II receptors. Pharmacol Rev 52:415–472
Diniz GP, Carneiro-Ramos MS, Barreto-Chaves ML (2007) Angiotensin type 1 (AT1) and type 2 (AT2) receptors mediate the increase in TGF-beta1 in thyroid hormone-induced cardiac hypertrophy. Pflugers Arch 454:75–81
Diniz GP, Carneiro-Ramos MS, Barreto-Chaves ML (2009) Angiotensin type 1 receptor mediates thyroid hormone-induced cardiomyocyte hypertrophy through the Akt/GSK-3beta/mTOR signaling pathway. Basic Res Cardiol 104:653–667
Dostal DE, Rothblum KN, Conrad KM, Cooper GR, Baker KM (1992) Detection of angiotensin I and II in cultured rat cardiac myocytes and fibroblasts. Am J Physiol 263:C851–C863
Eppenberger-Eberhardt M, Aigner S, Donath MY, Kurer V, Walther P, Zup**er C, Schaub MC, Eppenberger HM (1997) IGF-I and bFGF differentially influence atrial natriuretic factor and alpha-smooth muscle actin expression in cultured atrial compared to ventricular adult rat cardiomyocytes. J Mol Cell Cardiol 29:2027–2039
Fischer P, Hilfiker-Kleiner D (2007) Survival pathways in hypertrophy and heart failure: the gp130-STAT3 axis. Basic Res Cardiol 102:279–297
Gosteli-Peter MA, Harder BA, Eppenberger HM, Zapf J, Schaub MC (1996) Triiodothyronine induces over-expression of alpha-smooth muscle actin, restricts myofibrillar expansion and is permissive for the action of basic fibroblast growth factor and insulin-like growth factor I in adult rat cardiomyocytes. J Clin Invest 98:1737–1744
Horiuchi M, Akishita M, Dzau VJ (1999) Recent progress in angiotensin II type 2 receptor research in the cardiovascular system. Hypertension 33:613–621
Hu LW, Benvenuti LA, Liberti EA, Carneiro-Ramos MS, Barreto-Chaves ML (2003) Thyroxine-induced cardiac hypertrophy: influence of adrenergic nervous system versus renin–angiotensin system on myocyte remodeling. Am J Physiol Regul Integr Comp Physiol 285:R1473–R1480
Ichihara S, Senbonmatsu T, Price E Jr, Ichiki T, Gaffney FA, Inagami T (2001) Angiotensin II type 2 receptor is essential for left ventricular hypertrophy and cardiac fibrosis in chronic angiotensin II-induced hypertension. Circulation 104:346–351
Kahaly GJ, Dillmann WH (2005) Thyroid hormone action in the heart. Endocr Rev 26:704–728
Katz AM (2003) Pathophysiology of heart failure: identifying targets for pharmacotherapy. Med Clin North Am 87:303–316
Kenessey A, Ojamaa K (2006) Thyroid hormone stimulates protein synthesis in the cardiomyocyte by activating the Akt-mTOR and p70S6K pathways. J Biol Chem 281:20666–20672
Klein I (2003) Thyroid hormone and cardiac contractility. Am J Cardiol 91:1331–1332
Klein I (1990) Thyroid hormone and the cardiovascular system. Am J Med 88:631–637
Klein I (1988) Thyroxine-induced cardiac hypertrophy: time course of development and inhibition by propranolol. Endocrinology 123:203–210
Kobori H, Ichihara A, Miyashita Y, Hayashi M, Saruta T (1999) Local renin–angiotensin system contributes to hyperthyroidism-induced cardiac hypertrophy. J Endocrinol 160:43–47
Kobori H, Ichihara A, Suzuki H, Miyashita Y, Hayashi M, Saruta T (1997) Thyroid hormone stimulates renin synthesis in rats without involving the sympathetic nervous system. Am J Physiol 272:E227–E232
Kuzman JA, Vogelsang KA, Thomas TA, Gerdes AM (2005) l-Thyroxine activates Akt signaling in the heart. J Mol Cell Cardiol 39:251–258
Levy BI, Benessiano J, Henrion D, Caputo L, Heymes C, Duriez M, Poitevin P, Samuel JL (1996) Chronic blockade of AT2-subtype receptors prevents the effect of angiotensin II on the rat vascular structure. J Clin Invest 98:418–425
Lindpaintner K, Lu W, Neidermajer N, Schieffer B, Just H, Ganten D, Drexler H (1993) Selective activation of cardiac angiotensinogen gene expression in post-infarction ventricular remodeling in the rat. J Mol Cell Cardiol 25:133–143
Liu YH, Yang XP, Sharov VG, Nass O, Sabbah HN, Peterson E, Carretero OA (1997) Effects of angiotensin-converting enzyme inhibitors and angiotensin II type 1 receptor antagonists in rats with heart failure. Role of kinins and angiotensin II type 2 receptors. J Clin Invest 99:1926–1935
Mifune M, Sasamura H, Shimizu-Hirota R, Miyazaki H, Saruta T (2000) Angiotensin II type 2 receptors stimulate collagen synthesis in cultured vascular smooth muscle cells. Hypertension 36:845–850
Miki T, Miura T, Tanno M, Nishihara M, Naitoh K, Sato T, Takahashi A, Shimamoto K (2007) Impairment of cardioprotective PI3K-Akt signaling by post-infarct ventricular remodeling is compensated by an ERK-mediated pathway. Basic Res Cardiol 102:163–170
Morgan HE, Baker KM (1991) Cardiac hypertrophy. Mechanical, neural, and endocrine dependence. Circulation 83:13–25
Nouet S, Amzallag N, Li JM, Louis S, Seitz I, Cui TX, Alleaume AM, Di Benedetto M, Boden C, Masson M, Strosberg AD, Horiuchi M, Couraud PO, Nahmias C (2004) Trans-inactivation of receptor tyrosine kinases by novel angiotensin II AT2 receptor-interacting protein, ATIP. J Biol Chem 279:28989–28997
Oudit GY, Penninger JM (2009) Cardiac regulation by phosphoinositide 3-kinases and PTEN. Cardiovasc Res 82:250–260
Pantos C, Mourouzis I, Markakis K, Tsagoulis N, Panagiotou M, Cokkinos DV (2008) Long-term thyroid hormone administration reshapes left ventricular chamber and improves cardiac function after myocardial infarction in rats. Basic Res Cardiol 103:308–318
Pantos C, Mourouzis I, **naris C, Papadopoulou-Daifoti Z, Cokkinos D (2008) Thyroid hormone and “cardiac metamorphosis”: potential therapeutic implications. Pharmacol Ther 118:277–294
Porrello ER, Delbridge LM, Thomas WG (2009) The angiotensin II type 2 (AT2) receptor: an enigmatic seven transmembrane receptor. Front Biosci 14:958–972
Sadoshima J, Izumo S (1993) Molecular characterization of angiotensin II-induced hypertrophy of cardiac myocytes and hyperplasia of cardiac fibroblasts. Critical role of the AT1 receptor subtype. Circ Res 73:413–423
Santos RA, Simoes e Silva AC, Maric C, Silva DM, Machado RP, de Buhr I, Heringer-Walther S, Pinheiro SV, Lopes MT, Bader M, Mendes EP, Lemos VS, Campagnole-Santos MJ, Schultheiss HP, Speth R, Walther T (2003) Angiotensin-(1–7) is an endogenous ligand for the G protein-coupled receptor Mas. Proc Natl Acad Sci USA 100:8258–8263
Senbonmatsu T, Ichihara S, Price E Jr, Gaffney FA, Inagami T (2000) Evidence for angiotensin II type 2 receptor-mediated cardiac myocyte enlargement during in vivo pressure overload. J Clin Invest 106:R25–R29
Senbonmatsu T, Saito T, Landon EJ, Watanabe O, Price E Jr, Roberts RL, Imboden H, Fitzgerald TG, Gaffney FA, Inagami T (2003) A novel angiotensin II type 2 receptor signaling pathway: possible role in cardiac hypertrophy. EMBO J 22:6471–6482
Tsuzuki S, Matoba T, Eguchi S, Inagami T (1996) Angiotensin II type 2 receptor inhibits cell proliferation and activates tyrosine phosphatase. Hypertension 28:916–918
Tuxworth WJ Jr, Shiraishi H, Moschella PC, Yamane K, McDermott PJ, Kuppuswamy D (2008) Translational activation of 5′-TOP mRNA in pressure overload myocardium. Basic Res Cardiol 103:41–53
Yamada T, Horiuchi M, Dzau VJ (1996) Angiotensin II type 2 receptor mediates programmed cell death. Proc Natl Acad Sci USA 93:156–160
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This study received financial support in the form of grants from the Fundação de Amparo à Pesquisa do Estado de São Paulo (FAPESP, Foundation for the Support of Research in the State of São Paulo; grant nos. 01/11678-8 and 03/04638-8) and from the Conselho Nacional de Desenvolvimento Científico e Tecnológico (CNPq, National Council for Scientific and Technological Development).
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Carneiro-Ramos, M.S., Diniz, G.P., Nadu, A.P. et al. Blockage of Angiotensin II type 2 receptor prevents thyroxine-mediated cardiac hypertrophy by blocking Akt activation. Basic Res Cardiol 105, 325–335 (2010). https://doi.org/10.1007/s00395-010-0089-0
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DOI: https://doi.org/10.1007/s00395-010-0089-0