title: Contribution of serotonin to cardiac remodeling associated with hypertensive diastolic ventricular dysfunction in rats.
abstract: OBJECTIVE
  Left-ventricular hypertrophy and interstitial fibrosis are the main pathophysiological factors of heart failure with preserved ejection fraction. Blockade of the serotonin 5-HT2B receptor (5-HT2BR) has been shown to reduce cardiac hypertrophy, oxidative stress, and extracellular cell matrix activation. In this study, we evaluated the effects of the 5-HT2BR blockade, on hemodynamic and cardiac remodeling, in spontaneously hypertensive rats (SHRs) that display a diastolic dysfunction with preserved ejection fraction.
  
  
  METHODS
  Thirty-seven-week-old SHRs were randomized in four groups receiving either saline, the selective 5-HT2BR antagonist RS-127445 (1 mg/kg per day), a calcium channel blocker nicardipine (6 mg/kg per day), or RS-127445 + nicardipine. During the 14 weeks of treatment period, cardiac function and blood pressure were monitored by echocardiography and tail-cuff. Finally, electrocardiograms and invasive hemodynamics were obtained before blood collection. Heart was analyzed for morphology and mRNA expression. A complementary study evaluated the cardiac and vascular effects of serotonin on wild-type and mice knockout for the 5-HT2BR (Htr2B) and/or the 5-HT2AR (Htr2A).
  
  
  RESULTS
  Despite the left ventricular 5-HT2BR overexpression, 5-HT2BR blockade by RS-127445 did not affect left ventricular hypertrophy and fibrosis in SHRs. This antagonist did not improve diastolic dysfunction, neither alone nor in combination with nicardipine, although it induced plasma brain natriuretic peptide decrease. Moreover, RS-127445 amplified subendocardial fibrosis and favored left ventricular dilatation. Finally, a subendocardial left ventricular fibrosis was induced by chronic serotonin in wild-type mice, which was increased in Htr2B animals, but prevented in Htr2A and Htr2A/2B mice, and could be explained by a contribution of the endothelial 5-HT2BRs to coronary vasodilatation.
  
  
  CONCLUSIONS
  This work is the first to identify a cardioprotective function of the 5-HT2BR in an integrated model of diastolic dysfunction with preserved ejection fraction.
authors.affiliation: aLaboratoire de Neurobiologie et Pharmacologie Cardiovasculaire EA7296, Faculté de Médecine, Fédération de Médecine Translationnelle, Université et Centre Hospitalier de Strasbourg, Strasbourg bMouse Clinical Institute, Illkirch-Graffenstaden cCNRS, UMR7213, University of Strasbourg, Illkirch-Graffenstaden dINSERM U1063, Stress oxydant et pathologies métaboliques, LUNAM Université, Angers eINSERM UMR S-839, Institut du Fer à Moulin, Université Pierre et Marie Curie, 17 rue du Fer à Moulin, Paris, France *Estelle Ayme-Dietrich and Halim Marzak contributed equally to this work.
authors.forename: Estelle
authors.initials: E
authors.lastname: Ayme-Dietrich
authors.forename: Halim
authors.initials: H
authors.lastname: Marzak
authors.forename: Roland
authors.initials: R
authors.lastname: Lawson
authors.forename: Walid
authors.initials: W
authors.lastname: Mokni
authors.forename: Olivia
authors.initials: O
authors.lastname: Wendling
authors.forename: Roy
authors.initials: R
authors.lastname: Combe
authors.forename: Julien
authors.initials: J
authors.lastname: Becker
authors.forename: Lahcen
authors.initials: L
authors.lastname: El Fertak
authors.forename: Marie-France
authors.initials: MF
authors.lastname: Champy
authors.forename: Rachel
authors.initials: R
authors.lastname: Matz
authors.forename: Ramaroson
authors.initials: R
authors.lastname: Andriantsitohaina
authors.forename: Stéphane
authors.initials: S
authors.lastname: Doly
authors.forename: Katia
authors.initials: K
authors.lastname: Boutourlinsky
authors.forename: Luc
authors.initials: L
authors.lastname: Maroteaux
authors.forename: Laurent
authors.initials: L
authors.lastname: Monassier
mesh_terms: D000818:Animals; D001794:Blood Pressure / Q000187:drug effects* / Q000502:physiology; D004452:Echocardiography; D006333:Heart Failure / Q000378:metabolism / Q000503:physiopathology; D006352:Heart Ventricles / Q000187:drug effects / Q000378:metabolism / Q000503:physiopathology; D006973:Hypertension / Q000378:metabolism* / Q000503:physiopathology; D017379:Hypertrophy, Left Ventricular / Q000378:metabolism* / Q000503:physiopathology; D008297:Male; D051379:Mice; D018345:Mice, Knockout; D020097:Natriuretic Peptide, Brain / Q000378:metabolism; D011743:Pyrimidines / Q000494:pharmacology; D051381:Rats; D011918:Rats, Inbred SHR; D044402:Receptor, Serotonin, 5-HT2A / Q000235:genetics / Q000378:metabolism; D044403:Receptor, Serotonin, 5-HT2B / Q000235:genetics / Q000378:metabolism; D012701:Serotonin / Q000378:metabolism*; D012702:Serotonin Antagonists / Q000494:pharmacology*; D018487:Ventricular Dysfunction, Left / Q000378:metabolism* / Q000503:physiopathology
chemical_list: D011743:Pyrimidines; D044402:Receptor, Serotonin, 5-HT2A; D044403:Receptor, Serotonin, 5-HT2B; D012702:Serotonin Antagonists; C121466:2-amino-4-(4-fluoronaphth-1-yl)-6-isopropylpyrimidine; D020097:Natriuretic Peptide, Brain; D012701:Serotonin