Roles and controls of mTOR in the heart. Focus on “mTOR attenuates the inflammatory response in cardiomyocytes and prevents cardiac dysfunction in pathological hypertrophy”

Editorial FocusRoles and controls of mTOR in the heart. Focus on "mTOR attenuates the inflammatory response in cardiomyocytes and prevents cardiac dysfunction in pathological hypertrophy"Paul J. Davis, Faith B. Davis, and Hung-Yun LinPaul J. DavisOrdway Research Institute, Albany Medical College, and Albany College of Pharmacy, Albany, New York, Faith B. DavisOrdway Research Institute, , and Hung-Yun LinOrdway Research Institute, Published Online:01 Dec 2010https://doi.org/10.1152/ajpcell.00410.2010This is the final version - click for previous versionMoreSectionsPDF (612 KB)Download PDF ToolsExport citationAdd to favoritesGet permissionsTrack citations in their article in this issue, Song et al. (24) present evidence that mammalian target of rapamycin (mTOR), a serine-threonine kinase, is an endogenous suppressor of the inflammatory response that complicates myocardial hypertrophy induced by aortic constriction. This inflammatory process has been shown by others to contribute to cardiac dysfunction in models of myocardial hypertrophy (21) and in the clinical setting (27). Thus intrinsic suppression or, if feasible, pharmacological suppression of this inflammatory complication of pressure overload is desirable. The mechanism by which the inflammatory response is engendered is not fully understood, but several sets of cytokines have been implicated in models of cardiac hypertrophy (8, 26, 27). Song et al. (24) report that IL-6 and IL-1β are involved in the transverse aortic constriction (TAC) model of pressure overload-induced inflammation. They also show that hyperexpression of mTOR inhibits the appearance/release of the interleukins and the consequent development of inflammation. Rapamycin blocked the protective action of superinduction of mTOR.mTOR and Myocardial HypertrophyThat the roles of mTOR are complex in models of myocardial hypertrophy is shown by reports of pressure overload-induced hypertrophy in which the latter is reversed by rapamycin (5, 16) or the separate conclusions that mTOR need not be involved at all in the hypertrophic process (22) and that, as described by Song et al. (24), mTOR protects against hypertrophy-associated inflammation. The experimental characterization of the roles of mTOR in the stressed heart has usually and understandably depended on the use of rapamycin. However, both rapamycin-insensitive (10, 14) and rapamycin-sensitive mTOR-regulated transduction pathways exist in tissues. Furthermore, the unstimulated mTOR pathway, subjected to inhibition with rapamycin in the studies of McMullen et al. (16), Gao et al. (5), and others, may be quite different functionally from the hyperstimulated mTOR system obtained by transfection in the studies reported by Song et al. (24).The results of Song et al. (24) raise several important pathophysiological questions. For example, what are the endogenous mechanisms by which activity or abundance of mTOR is modulated? Are there endogenous or pharmacological inhibitors of mTOR that may act in the clinical setting to allow the inflammatory response to pressure overload to proceed and to promote heart failure?Endogenous Regulation of mTOR ActivityMa and Bienis (14) recently reviewed some of the factors that regulate activities of mTOR complex 1 and complex 2 signaling networks. Among these factors are insulin and insulin-like growth factor (IGF) polypeptides and cytokines (TNF-α). It is worthwhile, however, to point out that certain endogenous small molecules also may act in the heart via mTOR. These include thyroid hormone and sympathomimetics, testosterone, and a stilbene, resveratrol.Small Molecule Regulation of Cardiac mTOR: the Example of Thyroid HormoneThyroid hormone activates mTOR via the phosphatidylinositol 3-kinase signal transduction pathway in a variety of cells. This was originally demonstrated by Moeller et al. (17), who studied the actions of 3,5,3′-triiodo-l-thyronine (T3) in fibroblasts. T3 was found to act nongenomically via mTOR to cause the downstream gene transcription of ZAKI-4, a calcineurin inhibitor, and hypoxia-inducible factor-1α (HIF-1α). This is one of a number of interfaces now recognized between nongenomic and genomic actions of thyroid hormone (4). Other authors have confirmed that T3 activates mTOR (25), including cardiomyocyte mTOR (8, 10). Indeed, mTOR activation by thyroid hormone has been seen in two cardiac contexts: mediation of physiological growth supported by thyroid hormone (9) and as an essential to experimental myocardial hypertrophy caused by the hormone (11). Rapamycin can prevent cardiac hypertrophy induced by T3.From these several findings we can conclude that thyroid hormone, T3, is an endogenous activator of cardiac mTOR and that, when present in excess in an animal model, the hormone may contribute to the process of cardiac hypertrophy, as shown by Kuzman et al. (11) and Pantos et al. (19). The interpretation of these interesting reports should be tempered by the observation that T3 can also prevent the deleterious myocardial remodeling (fiber lengthening and cardiac dilatation) after myocardial infarction in the rat (2). The latter description may be consistent with the observations of Song et al. (24) that support a myocardioprotective role for mTOR, but Song et al. did not pursue the possibility that iodothyronines supported the action of mTOR in their models. Additional features of thyroid hormone-caused cardiac hypertrophy were recently reviewed by Ojamaa (18).There is also literature that suggests thyroid hormone can support the inflammatory process, and this is possibly related to the inflammation that may be encountered in the hypertrophic heart. T3 in nanomolar concentrations selectively increases IL-6 and IL-8 production by osteoblasts and bone marrow stromal cells (23) and IL-10 in dendritic cells (15). Furthermore, thyroid hormone potentiates actions of IFN-γ (12) and STAT-3 (13), an intracellular transducer of the signals of a number of cytokines. This literature provides a theoretical context in which to view thyroid hormone-induced myocardial hypertrophy and the report of Song et al. (24), namely, that the inflammatory process characteristic of TAC-induced cardiac enlargement is probably not a material contributor to the heart hypertrophy that is hormone-induced but is associated with impaired cardiac function that can complicate hypertrophy and that is inflammation related.Thus, in considering molecular mechanisms involved in mTOR actions in the heart, it may not only be necessary to distinguish between the rapamycin-inhibitable and rapamycin-independent mTOR signaling pathways but also to distinguish between uncomplicated hypertrophy and hypertrophy complicated by impaired cardiac function. If thyroid hormone plays a role in modulating the myocardial action of mTOR, then the stable physiological levels of thyroid hormone in the intact animal model may be permissive in terms of mTOR-mediated myocardial hypertrophy, but supraphysiological levels of the hormone may contribute to development of mTOR-associated inflammatory changes and dysfunction. It should be pointed out that the TAC model of pressure overload has not yet been examined in the settings of thyroid dysfunction to elucidate any possible contribution of this hormone to the cardiac inflammatory process.In models of induction of heart failure such as that related to postischemic remodeling, a pattern of nuclear thyroid hormone receptor (TR) change has been observed in which TRα1 is downregulated (19) as failure occurs. Circulating levels of T3 and T4 are not changed. A frank decrease in mTOR occurs concurrently with the decrease in TRα1 in this setting. The sympathomimetic phenylephrine (PE) increases nuclear TRα1 abundance, and this action of PE is blocked by rapamycin. We can thus conclude that PE and other sympathomimetics (3, 20) can activate mTOR, and we can also note that mTOR modulates expression of the TRα1 gene. The latter effect could alter tissue response to thyroid hormone without a change in the level of circulating hormone.Other Small Molecule Regulators of Cardiac mTORAre there other small molecules identified that can target mTOR, potentially for therapeutic purposes? The answer is yes. For example, the recent cancer literature informs us of the existence of multiple pharmacological inhibitors of mTOR that are under development (6). Thus, from the standpoint of its inhibition, mTOR is a druggable target. It is not clear that any of the oncologic drugs would be useful or safe or desirable in the context of the enlarged heart.From the standpoint of pharmacological stimulation of mTOR, the above discussion indicates that agents such as thyroid hormone or PE and other sympathomimetics may be the subject of further investigation as adjuncts in the management of cardiac hypertrophy or hypertrophy complicated by inflammation-dependent heart failure. Furthermore, testosterone can induce myocardial hypertrophy via activation of mTOR (1), but it is not yet clear whether this action has an inflammatory component. There is also recent evidence that resveratrol, a naturally occurring polyalcohol that has certain estrogen-like actions, as well as anti-aging and anti-cancer effects in animal models, is cardioprotective in an ischemic model by an mTOR-related, antiapoptotic mechanism (7). The mTOR-mediated actions on the heart of several endogenous small molecules (nonpeptide hormones and resveratrol) are briefly summarized in Fig. 1.Fig. 1.Selected mammalian target of rapamycin (mTOR)-mediated events in the myocardium. A: a model of Song et al. (24) is shown in which hyperexpression of mTOR protects cardiomyocytes against the inflammatory response that accompanies pressure overload and may condition cardiac dysfunction. It is not yet known what intracellular or extracellular factors may modulate mTOR activity in the model. B: examples of endogenous small molecules in the intact organism that regulate mTOR activity in the heart and promote diverse consequences that include cardiac hypertrophy or protection against ischemia. Acting via specific plasma membrane receptors, thyroid hormone and sympathomimetics activate mTOR and may induce hypertrophy. Testosterone experimentally also induces mTOR-dependent hypertrophy, possibly through a plasma membrane receptor. Resveratrol is a cardioprotectant, acting via mTOR. mTOR activation in response to resveratrol may be initiated at a specific plasma membrane receptor or in cytoplasm. It has yet to be determined whether such small molecules may modulate the cardiomyocyte response depicted in A.Download figureDownload PowerPointConclusionsA variety of pharmacological probes currently now exist to refine our understanding of the relationship of mTOR to heart mass, cardiac function, and inflammatory changes in the heart that may accompany hypertrophy and lead to dysfunction. It is clear from the observations of Song et al. (24) and from the foregoing discussion that a good deal more information is needed to define the experimental cardiologic circumstances in which mTOR stimulation works and when mTOR inhibition may be desirable for possible clinical applications. Some of the information that would be helpful includes determining whether the protection against cardiac inflammation afforded by increased mTOR is limited to the setting of hypertrophy or may be applied to the inflammatory response about infarction or in myocarditis syndromes. Do endogenous hormones in normal concentrations serve as permissive factors in mTOR-dependent hypertrophy or in the mTOR-mediated defense against inflammatory change? Does cardiomyocyte mTOR promote both physiological growth and hypertrophy? What are the circumstances in which cardiac hypertrophy does not involve mTOR?DISCLOSURESNo conflicts of interest, financial or otherwise, are declared by the author(s).REFERENCES1. Altamirano F , Oyarce C , Silva P , Toyos M , Wilson C , Lavandero S , Uhlen P , Estrada M. Testosterone induces cardiomyocyte hypertrophy through mammalian target of rapamycin complex 1 pathway. J Endocrinol 202: 299–307, 2009.Crossref | PubMed | ISI | Google Scholar2. Chen YF , Kobayashi S , Chen J , Redetzke RA , Said S , Liang Q , Gerdes AM. Short term triiodo-l-thyronine treatment inhibits cardiac myocyte apoptosis in border area after myocardial infarction in rats. J Mol Cell Cardiol 44: 180–187, 2008.Crossref | PubMed | ISI | Google Scholar3. Chenal J , Pellerin L. Noradrenaline enhances the expression of the neuronal monocarboxylate transporter MCT2 by translational activation via stimulation of PI3K/Akt and the mTOR/S6K pathway. J Neurochem 102: 389–397, 2007.Crossref | PubMed | ISI | Google Scholar4. Cheng SY , Leonard JL , Davis PJ. Molecular aspects of thyroid hormone actions. Endocr Rev 31: 139–170, 2010.Crossref | PubMed | ISI | Google Scholar5. Gao XM , Wong G , Wang B , Kiriazis H , Moore XL , Su YD , Dart A , Du XJ. Inhibition of mTOR reduces chronic pressure-overload cardiac hypertrophy and fibrosis. J Hypertens 24: 1663–1670.Crossref | PubMed | ISI | Google Scholar6. Granville CA , Memmott RM , Gills JJ , Dennis PA. Handicapping the race to develop inhibitors of the phosphatidylinositol 3-kinase/Akt/mammalian target of rapamycin pathway. Clin Cancer Res 12: 679–689.Crossref | PubMed | ISI | Google Scholar7. Gurusamy N , Lekli I , Mukherjee S , Ray D , Ahsan MK , Gerghiceanu M , Popescu LM , Das DK. Cardioprotection by resveratrol: a novel mechanism via autophagy involving the mTORC2 pathway. Cardiovasc Res 86: 103–112, 2010.Crossref | PubMed | ISI | Google Scholar8. Honshu S , Nishikawa S , Amano K , Zen K , Adachi Y , Kishita E , Matsui A , Katsume A , Yamaguchi S , Nishikawa K , Isoda K , Riches DW , Matoba S , Okigaki M , Matsubara H. Pressure-mediated hypertrophy and mechanical stretch induces IL-1 release and subsequent IGF-1 generation to maintain compensative hypertrophy by affecting Akt and JNK pathways. Circ Res 105: 1149–1158, 2009.Crossref | PubMed | ISI | Google Scholar9. Kennessey A , Ojamaa K. Thyroid hormone stimulates protein synthesis in the cardiomyocyte by activating the Akt-mTOR and p70S6K pathways. J Biol Chem 281: 20666–20672, 2006.Crossref | PubMed | ISI | Google Scholar10. Kristof AS , Marks-Konczalik J , Billings E , Moss J. Stimulation of signal transducer and activator of transcription-1 (STAT1)-dependent gene expression by lipopolysaccharide and interferon-γ is regulated by mammalian target of rapamycin. J Biol Chem 278: 33637–33644, 2003.Crossref | PubMed | ISI | Google Scholar11. Kuzman JA , O'Connell TD , Gerdes AM. Rapamycin prevents thyroid hormone-induced cardiac hypertrophy. Endocrinology 148: 3477–3484, 2007.Crossref | PubMed | ISI | Google Scholar12. Lin HY , Martino LJ , Wilcox BD , Davis FB , Gordinier JK , Davis PJ. Potentiation by thyroid hormone of human IFN-γ-induced HLA-DR expression. J Immunol 161: 843–849.PubMed | ISI | Google Scholar13. Lin HY , Shih A , Davis FB , Davis PJ. Thyroid hormone promotes the phosphorylation of STAT3 and potentiates the action of epidermal growth factor in cultured cells. Biochem J 338: 427–432.Crossref | PubMed | ISI | Google Scholar14. Ma XM , Bienis J. Molecular mechanisms of mTOR-mediated translational control. Nat Rev Mol Cell Biol 10: 307–318, 2009.Crossref | PubMed | ISI | Google Scholar15. Mascanfroni I , del Mar Montesinos M , Susperreguy S , Cervi L , Ilarregui JM , Ramseyer VD , Masini-Repiso AM , Targovnik HM , Rabinovich GA , Pellizas CG. Control of dendritic cell maturation and function by triiodothyronine. FASEB J 22: 1032–1042, 2008.Crossref | PubMed | ISI | Google Scholar16. McMullen JR , Sherwood MC , Tarnavski O , Zhang L , Dorfman AL , Shiol T , Izumo S. Inhibition of mTOR signaling with rapamycin regresses established cardiac hypertrophy induced by pressure overload. Circulation 109: 3050–3055.Crossref | PubMed | ISI | Google Scholar17. Moeller LC , Cao X , Dumitrescu AM , Seo H , Refetoff S. Thyroid hormone mediated changes in gene expression can be initiated by cytosolic action of the thyroid hormone receptor β through the phosphatidylinositol 3-kinase pathway. Nucl Recept Signal 4: e020, 2006.Crossref | PubMed | Google Scholar18. Ojamaa K. Signaling mechanisms in thyroid hormone-induced cardiac hypertrophy. Vascul Pharmacol 52: 113–119, 2010.Crossref | PubMed | ISI | Google Scholar19. Pantos C , Mourouzis I , Galanopoulos G , Gavra M , Perimenis P , Spanou D , Cokkinos DV. Thyroid hormone receptor α1 downregulation in postischemic heart failure progression: the potential role of tissue hypothyroidism. Horm Metab Res 42: 718–724, 2010.Crossref | PubMed | ISI | Google Scholar20. Pesce L , Comellas A , Sznajder JI. Beta-adrenergic agonists regulate Na-K-ATPase via p70S6k. Am J Physiol Lung Cell Mol Physiol 285: L802–L807, 2003.Link | ISI | Google Scholar21. Serra Santos MH AJ , Bocalini DS , Antonio EL , Levy RF , Sanatos AA , Higuchi ML , Silva JA , Magalhaes FC , Barauna VG , Krieger JE , Tucci PJ. Exercise training inhibits inflammatory cytokines and more than prevents myocardial dysfunction in rats with sustained β-adrenergic hyperactivity. J Physiol 588: 2431–2441, 2010.Crossref | PubMed | ISI | Google Scholar22. Shen WH , Chen Z , Shi S , Chen H , Zhu W , Penner A , Bu G , Li W , Boyle DW , Rubart M , Field LJ , Abraham R , Liechty EA , Shou W. Cardiac restricted overexpression of kinase-dead mammalian target of rapamycin (mTOR) mutant impairs the mTOR-mediated signaling and cardiac function. J Biol Chem 283: 13842–13849, 2008.Crossref | PubMed | ISI | Google Scholar23. Siddiqi A , Burrin JM , Wood DF , Monson JP. Tri-iodothyronine regulates the production of interleukin-8 in human bone marrow stromal and osteoblast-like cells. J Endocrinol 157: 453–461, 1998.Crossref | PubMed | ISI | Google Scholar24. Song X , Kusakari Y , Xiao CY , Kinsella SD , Rosenberg MA , Scherrer-Crosbie M , Hara K , Rosenzweig Matsui T. mTOR attenuates the inflammatory response in cardiomyocytes and prevents cardiac dysfunction in pathological hypertrophy. Am J Physiol Cell Physiol (September 22, 2010). doi:10.1152/ajpcell.00338.2010.Link | ISI | Google Scholar25. Sui Wang JL , Li BM. Administration of triiodo-l-thyronine into dorsal hippocampus alters phosphorylation of Akt, mammalian target of rapamycin, p70S6 kinase and 4E-BP1 in rats. Neurochem Res 33: 1065–1076, 2008.Crossref | PubMed | ISI | Google Scholar26. Vistnes M , Waehre A , Nygard S , Sjaastad I , Andersson KB , Husberg C , Christensen G. Circulating cytokine levels in mice with heart failure are etiology dependent. J Appl Physiol 108: 1357–1364, 2010.Link | ISI | Google Scholar27. Yndestad A , Damas JK , Oie E , Ueland T , Gullestad L , Aukrust P. Role of inflammation in the progression of heart failure. Curr Cardiol Rep 9: 236–241, 2007.Crossref | PubMed | Google ScholarAUTHOR NOTESAddress for reprint requests and other correspondence: P. J. Davis, Ordway Research Institute, 150 New Scotland Ave., Albany, NY 12208 (e-mail: [email protected]org). Download PDF Previous Back to Top Next FiguresReferencesRelatedInformation Cited ByNongenomic effects of thyroid hormones on the immune system cells: New targets, old playersSteroids, Vol. 77, No. 10Overlapping nongenomic and genomic actions of thyroid hormone and steroidsSteroids, Vol. 31 More from this issue > Volume 299Issue 6December 2010Pages C1250-C1252 Copyright & PermissionsCopyright © 2010 the American Physiological Societyhttps://doi.org/10.1152/ajpcell.00410.2010PubMed20926776History Received 4 October 2010 Accepted 4 October 2010 Published online 1 December 2010 Published in print 1 December 2010 Metrics