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Journal of Neural Transmission

, Volume 120, Issue 6, pp 927–935 | Cite as

Role of serotonin 5-HT2A receptors in the development of cardiac hypertrophy in response to aortic constriction in mice

  • O. Lairez
  • T. Cognet
  • S. Schaak
  • D. Calise
  • C. Guilbeau-Frugier
  • A. Parini
  • J. Mialet-Perez
Translational Neurosciences - Original Article

Abstract

Serotonin, in addition to its fundamental role as a neurotransmitter, plays a critical role in the cardiovascular system, where it is thought to be involved in the development of cardiac hypertrophy and failure. Indeed, we recently found that mice with deletion of monoamine oxidase A had enhanced levels of blood and cardiac 5-HT, which contributed to exacerbation of hypertrophy in a model of experimental pressure overload. 5-HT2A receptors are expressed in the heart and mediate a hypertrophic response to 5-HT in cardiac cells. However, their role in cardiac remodeling in vivo and the signaling pathways associated are not well understood. In the present study, we evaluated the effect of a selective 5-HT2A receptor antagonist, M100907, on the development of cardiac hypertrophy induced by transverse aortic constriction (TAC). Cardiac 5-HT2A receptor expression was transiently increased after TAC, and was recapitulated in cardiomyocytes, as observed with 5-HT2A in situ labeling by immunohistochemistry. Selective blockade of 5-HT2A receptors prevented the development of cardiac hypertrophy, as measured by echocardiography, cardiomyocyte area and heart weight-to-body weight ratio. Interestingly, activation of calmodulin kinase (CamKII), which is a core mechanism in cardiac hypertrophy, was reduced in cardiac samples from M100907-treated TAC mice compared to vehicle-treated mice. In addition, phosphorylation of histone deacetylase 4 (HDAC4), a downstream partner of CamKII was significantly diminished in M100907-treated TAC mice. Thus, our results show that selective blockade of 5-HT2A receptors has beneficial effect in the development of cardiac hypertrophy through inhibition of the CamKII/HDAC4 pathway.

Keywords

Serotonin 5-HT2A receptor M100907 Heart Hypertrophy 

Notes

Acknowledgments

This work was supported by grants from Institut National de la Santé et de la Recherche Médicale (INSERM), Agence Nationale pour la Recherche (ANR CARDIOMAO), Région Midi-Pyrénées and Université Paul Sabatier (Bonus Qualité Recherche). We thank J.J. Maoret (IFR150, Molecular Biology Platform), C. Delage (IFR 150, Microsurgery Platform) for their excellent technological assistance.

References

  1. Anderson ME, Brown JH, Bers DM (2011) CaMKII in myocardial hypertrophy and heart failure. J Mol Cell Cardiol 51(4):468–473PubMedCrossRefGoogle Scholar
  2. Brattelid T, Qvigstad E, Birkeland JA, Swift F, Bekkevold SV, Krobert KA, Sejersted OM, Skomedal T, Osnes JB, Levy FO, Sjaastad I (2007) Serotonin responsiveness through 5-HT2A and 5-HT4 receptors is differentially regulated in hypertrophic and failing rat cardiac ventricle. J Mol Cell Cardiol 43(6):767–779PubMedCrossRefGoogle Scholar
  3. Bush E, Fielitz J, Melvin L, Martinez-Arnold M, McKinsey TA, Plichta R, Olson EN (2004) A small molecular activator of cardiac hypertrophy uncovered in a chemical screen for modifiers of the calcineurin signaling pathway. Proc Natl Acad Sci USA 101(9):2870–2875PubMedCrossRefGoogle Scholar
  4. Cobo C, Alcocer L, Chavez A (1990) Effects of ketanserin on left ventricular hypertrophy in hypertensive patients. Cardiovasc Drugs Ther 4(Suppl 1):73–76PubMedCrossRefGoogle Scholar
  5. Cote F, Fligny C, Fromes Y, Mallet J, Vodjdani G (2004) Recent advances in understanding serotonin regulation of cardiovascular function. Trends Mol Med 10(5):232–238PubMedCrossRefGoogle Scholar
  6. Jaffre F, Callebert J, Sarre A, Etienne N, Nebigil CG, Launay JM, Maroteaux L, Monassier L (2004) Involvement of the serotonin 5-HT2B receptor in cardiac hypertrophy linked to sympathetic stimulation: control of interleukin-6, interleukin-1beta, and tumor necrosis factor-alpha cytokine production by ventricular fibroblasts. Circulation 110(8):969–974PubMedCrossRefGoogle Scholar
  7. Jaffre F, Bonnin P, Callebert J, Debbabi H, Setola V, Doly S, Monassier L, Mettauer B, Blaxall BC, Launay JM, Maroteaux L (2009) Serotonin and angiotensin receptors in cardiac fibroblasts coregulate adrenergic-dependent cardiac hypertrophy. Circ Res 104(1):113–123PubMedCrossRefGoogle Scholar
  8. Kehne JH, Baron BM, Carr AA, Chaney SF, Elands J, Feldman DJ, Frank RA, van Giersbergen PL, McCloskey TC, Johnson MP, McCarty DR, Poirot M, Senyah Y, Siegel BW, Widmaier C (1996) Preclinical characterization of the potential of the putative atypical antipsychotic MDL 100,907 as a potent 5-HT2A antagonist with a favorable CNS safety profile. J Pharmacol Exp Ther 277(2):968–981PubMedGoogle Scholar
  9. Knight AR, Misra A, Quirk K, Benwell K, Revell D, Kennett G, Bickerdike M (2004) Pharmacological characterisation of the agonist radioligand binding site of 5-HT(2A), 5-HT(2B) and 5-HT(2C) receptors. Naunyn Schmiedebergs Arch Pharmacol 370(2):114–123PubMedCrossRefGoogle Scholar
  10. Lairez O, Calise D, Bianchi P, Ordener C, Spreux-Varoquaux O, Guilbeau-Frugier C, Escourrou G, Seif I, Roncalli J, Pizzinat N, Galinier M, Parini A, Mialet-Perez J (2009) Genetic deletion of MAO-A promotes serotonin-dependent ventricular hypertrophy by pressure overload. J Mol Cell Cardiol 46(4):587–595PubMedCrossRefGoogle Scholar
  11. Liang YJ, Lai LP, Wang BW, Juang SJ, Chang CM, Leu JG, Shyu KG (2006) Mechanical stress enhances serotonin 2B receptor modulating brain natriuretic peptide through nuclear factor-kappaB in cardiomyocytes. Cardiovasc Res 72(2):303–312PubMedCrossRefGoogle Scholar
  12. Ling H, Zhang T, Pereira L, Means CK, Cheng H, Gu Y, Dalton ND, Peterson KL, Chen J, Bers D, Brown JH (2009) Requirement for Ca2+/calmodulin-dependent kinase II in the transition from pressure overload-induced cardiac hypertrophy to heart failure in mice. J Clin Invest 119(5):1230–1240PubMedCrossRefGoogle Scholar
  13. Marek GJ, Martin-Ruiz R, Abo A, Artigas F (2005) The selective 5-HT2A receptor antagonist M100907 enhances antidepressant-like behavioral effects of the SSRI fluoxetine. Neuropsychopharmacology 30(12):2205–2215PubMedCrossRefGoogle Scholar
  14. Mialet-Perez J, Bianchi P, Kunduzova O, Parini A (2007) New insights on receptor-dependent and monoamine oxidase-dependent effects of serotonin in the heart. J Neural Transm 114(6):823–827PubMedCrossRefGoogle Scholar
  15. Mialet-Perez J, D’Angelo R, Villeneuve C, Ordener C, Negre-Salvayre A, Parini A, Vindis C (2012) Serotonin 5-HT2A receptor-mediated hypertrophy is negatively regulated by caveolin-3 in cardiomyoblasts and neonatal cardiomyocytes. J Mol Cell Cardiol 52(2):502–510PubMedCrossRefGoogle Scholar
  16. Monassier L, Laplante MA, Jaffre F, Bousquet P, Maroteaux L, de Champlain J (2008) Serotonin 5-HT(2B) receptor blockade prevents reactive oxygen species-induced cardiac hypertrophy in mice. Hypertension 52(2):301–307PubMedCrossRefGoogle Scholar
  17. Nigmatullina RR, Kirillova VV, Jourjikiya RK, Mukhamedyarov MA, Kudrin VS, Klodt PM, Palotas A (2009) Disrupted serotonergic and sympathoadrenal systems in patients with chronic heart failure may serve as new therapeutic targets and novel biomarkers to assess severity, progression and response to treatment. Cardiology 113(4):277–286PubMedCrossRefGoogle Scholar
  18. Qvigstad E, Sjaastad I, Brattelid T, Nunn C, Swift F, Birkeland JA, Krobert KA, Andersen GO, Sejersted OM, Osnes JB, Levy FO, Skomedal T (2005) Dual serotonergic regulation of ventricular contractile force through 5-HT2A and 5-HT4 receptors induced in the acute failing heart. Circ Res 97(3):268–276PubMedCrossRefGoogle Scholar
  19. Rajesh KG, Suzuki R, Maeda H, Murio Y, Sasaguri S (2006) 5-HT2 receptor blocker sarpogrelate prevents downregulation of antiapoptotic protein Bcl-2 and protects the heart against ischemia-reperfusion injury. Life Sci 79(18):1749–1755PubMedCrossRefGoogle Scholar
  20. Sanganalmath SK, Barta J, Takeda N, Kumamoto H, Dhalla NS (2008) Antiplatelet therapy mitigates cardiac remodeling and dysfunction in congestive heart failure due to myocardial infarction. Can J Physiol Pharmacol 86(4):180–189PubMedCrossRefGoogle Scholar
  21. Villeneuve C, Caudrillier A, Ordener C, Pizzinat N, Parini A, Mialet-Perez J (2009) Dose-dependent activation of distinct hypertrophic pathways by serotonin in cardiac cells. Am J Physiol Heart Circ Physiol 297(2):H821–H828PubMedCrossRefGoogle Scholar
  22. Vindis C, D’Angelo R, Mucher E, Negre-Salvayre A, Parini A, Mialet-Perez J (2010) Essential role of TRPC1 channels in cardiomyoblasts hypertrophy mediated by 5-HT2A serotonin receptors. Biochem Biophys Res Commun 391(1):979–983. doi: 10.1016/j.bbrc.2009.12.001 PubMedCrossRefGoogle Scholar
  23. Vyssoulis GP, Karpanou EA, Pitsavos CE, Paleologos AA, Kourtis TK, Toutouzas PK (1990) Left ventricular hypertrophy regression and function changes with ketanserin in elderly hypertensives. Cardiovasc Drugs Ther 4(Suppl 1):81–84PubMedCrossRefGoogle Scholar
  24. Xie HH, Shen FM, Cao YB, Li HL, Su DF (2005) Effects of low-dose ketanserin on blood pressure variability, baroreflex sensitivity and end-organ damage in spontaneously hypertensive rats. Clin Sci (Lond) 108(6):547–552CrossRefGoogle Scholar
  25. Yabanoglu S, Akkiki M, Séguélas MH, Mialet-Perez J, Parini A, Pizzinat N (2009) Platelet derived serotonin drives the activation of rat cardiac fibroblasts by 5-HT2A receptors. J Mol Cell Cardiol 46(4):518–525PubMedCrossRefGoogle Scholar

Copyright information

© Springer-Verlag Wien 2013

Authors and Affiliations

  • O. Lairez
    • 1
    • 3
  • T. Cognet
    • 1
    • 3
  • S. Schaak
    • 2
    • 3
  • D. Calise
    • 1
    • 3
  • C. Guilbeau-Frugier
    • 1
    • 3
  • A. Parini
    • 1
    • 3
  • J. Mialet-Perez
    • 1
    • 3
  1. 1.INSERM UMR 1048, Institut des Maladies Métaboliques et CardiovasculairesToulouse Cedex 4France
  2. 2.EA 4564-Modélisation de l’Agression Tissulaire et de la Nociception (MATN)ToulouseFrance
  3. 3.Université Paul SabatierToulouseFrance

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