0235: Contribution of endothelial cells, serotonergic 5-HT2A and 5-HT2B receptors and eNOS in early processes of valve degeneration due to nordexfenfluramine in mice

Chronic use of 5-HT2B receptor (5-HT2B-R) agonists (anorectic drugs or ergot derivatives) has been associated with left cardiac valve injury but the mechanisms are unclear. Lesions are characterised by increased thickness and cellularity with massive extracellular matrix production. This work was designed to study contribution of 5-HT2B and 5-HT2A-R and the link with their activation and endothelial nitric oxide in valve degeneration. We validated an experimental mouse model of valvulopathy by infusing (28 days; Alzet® pumps) the selective 5-HT2B-R agonist (nordexfenfluramine: NdF 1mg/kg/day) and designed 13 groups: 5 groups of WT mice (129svPas; 12 weeks): 1) control (C); 2) NdF; 3) NdF+ritanserine (2mg/kg/day); 4) NdF+SB206553 (1mg/kg/day); 5) NdF+LNAME (300mg/kg/day); 8 groups of transgenics: 6) 5-HT2B-/--C; 7) 5-HT2B-/-- NdF; 8) 5-HT2A/2B-/--C; 9) 5-HT2A/2B-/--NdF; 10) 5-HT2A-/--C and 11) 5-HT2A-/-- NdF and 2 groups of eNOS-/- mice 12) eNOS-/--C and 13) eNOS-/--NdF. Mice were monitored for hemodynamic and echocardiographic parameters. At day 28, blood 5-HT and urinary 5-HIAA concentrations were measured and hearts harvested for histological analysis. In controls, this analysis reveals mitral valve lesions with increased thickness (WT-C 35±4μm vs WT-NdF 69±9μm; p