Abstract
Mitral Valve Prolapse (MVP) affects 3% of the population and is characterized by a heterogeneous mitral leaflet remodeling. The pathophysiological mechanisms involved in MVP are not fully understood, the only therapeutic option remains the surgical valve replacement. We previously identified FLNA as the first gene causing MVP and generated a unique knock-in rat model for the FLNA-P637Q mutation. The aim of our study was to characterize the morphological, functional and molecular expression of the valvular disease in our KI rat model. Five WT and 10 KI rats were evaluated at 3, 6 and 13 weeks. Comprehensive 2D echocardiography was performed to determine valve function and morphology. 3D analysis of the mitral valve (MV) remodelling was done using micro computed tomography (μCT). MV tissue composition was analyzed by histology. Transcriptomic comparison was performed using RNA-sequencing. Echocardiographic assessment confirmed the presence of MVP and elongated anterior leaflet in KI comparatively to WT rats (+12 to +14% at all time points P < 0.01)]. This was corroborated by an increased leaflets volume quantified by μCT (+20 to +58% in KI vs. WT all time points P < 0.05). Histological analyses revealed a myxomatous valve disease in KI rats. RNAseq unveiled that genes part of “cell chemotaxis” GO term (GO :0060326, P = 2.31 × 10 −5 ) including Ccl12 and S100a8 were significantly upregulated (+2.44x, +8.40x, respectively). As were Klf4 (+1.31x) and Tgfbr1 (+1.21x) for “endothelial cell migration” (GO:0043542, P = 1.59 × 10 −6 ) . Genes part of the GO:0048771 “tissue remodelling” ( P = 5.52 × 10 −5 ) were also found upregulated. These results establish that the KI FLNA-P637Q rat constitutes a pertinent model to study the pathophysiological molecular mechanisms associated with MVP. Our results point to pathways including inflammation and epithelial activation, which constitute potential therapeutic targets.
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