title: Serotonin markers show altered transcription levels in an experimental pig model of mitral regurgitation.
abstract: Serotonin (5-hydroxytryptamine, 5-HT) signalling is implicated in the pathogenesis of myxomatous mitral valve disease (MMVD) through 5-HT1B receptor (R), 5-HT2AR and 5-HT2BR-induced myxomatous pathology. Based on increased tryptophan hydroxylase-1 (TPH-1) and decreased serotonin re-uptake transporter (SERT) in MMVD-affected valves, increased valvular 5-HT synthesis and decreased clearance have been suggested. It remains unknown how haemodynamic changes associated with mitral regurgitation (MR) affect 5-HT markers in the mitral valve, myocardium and circulation. Twenty-eight pigs underwent surgically induced MR or sham-operation, resulting in three MR groups: control (CON, n = 12), mild MR (mMR, n = 10) and severe MR (sMR, n = 6). The gene expression levels of 5-HT1BR, 5-HT2AR, 5-HT2BR, SERT and TPH-1 were analysed using quantitative PCR (qPCR) in the mitral valve (MV), anterior papillary muscle (AP) and left ventricle (LV). MV 5-HT2BR was also analysed with immunohistochemistry (IHC) in relation to histological lesions and valvular myofibroblasts. All 5-HTR mRNAs were up-regulated in MV compared to AP and LV (P <0.01). In contrast, SERT and TPH-1 were up-regulated in AP and LV compared to MV (P <0.05). In MV, mRNA levels were increased for 5-HT2BR (P = 0.02) and decreased for SERT (P = 0.03) in sMR vs. CON. There were no group differences in 5-HT2BR staining (IHC) but co-localisation was found with α-SMA-positive cells in 91% of all valves and with 33% of histological lesions. In LV, 5-HT1BR mRNA levels were increased in sMR vs. CON (P = 0.01). In conclusion, these data suggest that MR may affect mRNA expression of valvular 5-HT2BR and SERT, and left ventricular 5-HT1BR in some pigs.
authors.affiliation: Department of Veterinary Disease Biology, University of Copenhagen, Frederiksberg, Denmark.
authors.forename: S E
authors.initials: SE
authors.lastname: Cremer
authors.affiliation: Department of Clinical Biochemistry, Copenhagen University Hospital Rigshospitalet, Copenhagen, Denmark.
authors.forename: N E
authors.initials: NE
authors.lastname: Zois
authors.affiliation: Novo Nordisk A/S, Maaloev, Denmark.
authors.forename: S G
authors.initials: SG
authors.lastname: Moesgaard
authors.affiliation: Department of Cardiothoracic and Vascular Surgery, Aarhus University Hospital, Aarhus, Denmark.
authors.forename: N
authors.initials: N
authors.lastname: Ravn
authors.affiliation: Department of Veterinary Clinical and Animal Sciences, University of Copenhagen, Frederiksberg, Denmark.
authors.forename: S
authors.initials: S
authors.lastname: Cirera
authors.affiliation: Department of Cardiothoracic and Vascular Surgery, Aarhus University Hospital, Aarhus, Denmark.
authors.forename: J L
authors.initials: JL
authors.lastname: Honge
authors.affiliation: Department of Cardiothoracic and Vascular Surgery, Aarhus University Hospital, Aarhus, Denmark.
authors.forename: M H
authors.initials: MH
authors.lastname: Smerup
authors.affiliation: Department of Cardiothoracic and Vascular Surgery, Aarhus University Hospital, Aarhus, Denmark.
authors.forename: J M
authors.initials: JM
authors.lastname: Hasenkam
authors.affiliation: Department of Anaesthesiology and Intensive Care Medicine, Aarhus University Hospital, Aarhus, Denmark.
authors.forename: E
authors.initials: E
authors.lastname: Sloth
authors.affiliation: Department of Veterinary Disease Biology, University of Copenhagen, Frederiksberg, Denmark.
authors.forename: P S
authors.initials: PS
authors.lastname: Leifsson
authors.affiliation: Department of Veterinary Disease Biology, University of Copenhagen, Frederiksberg, Denmark.
authors.forename: T
authors.initials: T
authors.lastname: Falk
authors.affiliation: Department of Clinical Studies, University of Pennsylvania, Philadelphia, PA, USA.
authors.forename: M A
authors.initials: MA
authors.lastname: Oyama
authors.affiliation: Department of Clinical Sciences, Colorado State University, Fort Collins, CO, USA.
authors.forename: C
authors.initials: C
authors.lastname: Orton
authors.affiliation: Department of Biostatistics, University of Copenhagen, Copenhagen, Denmark.
authors.forename: T
authors.initials: T
authors.lastname: Martinussen
authors.affiliation: Department of Veterinary Disease Biology, University of Copenhagen, Frederiksberg, Denmark. Electronic address: lisbeth.hoier@sund.ku.dk.
authors.forename: L H
authors.initials: LH
authors.lastname: Olsen
mesh_terms: D000818:Animals; D005260:Female; D005786:Gene Expression Regulation; D006321:Heart / Q000503:physiopathology; D006351:Heart Valves / Q000378:metabolism* / Q000503:physiopathology; D008944:Mitral Valve Insufficiency / Q000209:etiology / Q000235:genetics* / Q000378:metabolism; D009206:Myocardium / Q000378:metabolism*; D012701:Serotonin / Q000235:genetics* / Q000378:metabolism; D013552:Swine
chemical_list: D012701:Serotonin
keywords: 5-HT(2B) receptor; 5-Hydroxytrypatmine; Myxomatous mitral valve disease; Pig animal model; Serotonin