Activated Platelets enhance the Progression Of Calcific Aortic Valve Stenosis
Rihab BOUCHAREB1, Marie-Chloe Boulanger2, Lionel Taste1, Ghada Mkannez1, Mohamed J Nsaibia1, Fayez Hadji1, Abdellaziz Dahou1, Younes Messaddeq3, Benoit J Arsenault1, Philippe Pibarot1, Yohan Bosse1, Andre Marette1, Patrick Mathieu1.
1quebec heart and lung institute, quebec, QC, Canada, 2Quebec heart and lung institute, quebec, QC, Canada, 3Laval university, quebec, QC, Canada.
Introduction: Calcific aortic valve stenosis (CAVS) is a chronic disorder characterized by ectopic mineralization. Studies have shown that circulating platelets are activated during CAVS. However, whether platelets are actively involved into the pathobiology of CAVS is presently unknown. We have recently showed that autotaxin (ATX), which is secreted by valve interstitial cells (VICs), promotes the production of lysophosphatidic acid (LPA) with pro-osteogenic activity. objectif: We hypothesized that platelets could interact with ATX and promote the production of LPA and the osteogenic transition of VICs. Methods: Explanted human and mouse [LDLR-/- apoB100/100 IGFII (IGFII)] calcified aortic valves (AVs) were analysed by scanning electron microscope (SEM). We investigated in vitro the mechanisms by which platelets promote VIC mineralization. These results were validated in a mouse model of CAVS. Results: SEM analyses revealed the presence of activated platelets expressing GPIIbIIIa at the surface of calcified AVs (human and mouse) where the endothelium was activated or denuded. A treatment of VICs with activated human platelets significantly increased the mineralization compared to control. The mineralization was accompanied by an overexpression of osteogenic markers (RUNX2, BGLAP, ALP, and BMP2). Treatment of VICs with activated platelets increased significantly the enzymatic activity of ATX. Accordingly, ATX inhibition by HA130 or a siRNA significantly decreased platelet-induced VIC mineralization. In addition, blocking LPA receptors (LPARs) also inhibited platelet-induced calcification. In binding assay, ATX secreted by VICs interacted with platelets leading to the production of LPA. Inhibition of GPIIbIIIa prevented the interaction of ATX with platelets and the mineralization of VIC cultures. In IGFII mice, the intravenous injection of activated platelets accelerated the development of CAVS, whereas a Lpar1-3 blocker prevented the rise of transaortic velocities. Conclusion: Activated platelets are present in mineralized AVs and interact with ATX in promoting an osteogenic program. This work has potential clinical implications since it suggests that the pharmacological manipulation of ATX-platelet axis could prevent the mineralization of the AV.
Back to 2018 Program