Autotaxin Derived From Lipoprotein(a) and Valve Interstitial Cells Promotes Inflammation and Mineralization of the Aortic Valve
|Authors:||Bouchareb, Rihab; Mahmut, Ablajan; Nsaibia, Mohamed Jallaoul; Boulanger, Marie-Chloé; Dahou, Abdellaziz; Lépine, Jamie-Lee; Laflamme, Marie-Hélène; Hadji, Fayez; Couture, Christian; Trahan, Sylvain; Pagé, Sylvain; Bossé, Yohan; Pibarot, Philippe; Scipione, Corey A.; Romagnuolo, Rocco; Koschinsky, Marlys L.; Arsenault, Benoit; Marette, André; Mathieu, Patrick|
|Abstract:||Background—Mendelian randomization studies have highlighted that lipoprotein(a) [Lp(a)] was associated with calcific aortic valve disease (CAVD). Lp(a) transports oxidized phospholipids (OxPLs) with a high content in lysophosphatidylcholine (LPC). Autotaxin (ATX) transforms LPC into lysophosphatidic acid. We hypothesized that ATX-lysophosphatidic acid could promote inflammation/mineralization of the aortic valve. Methods and Results—We have documented the expression of ATX in control and mineralized aortic valves. By using different approaches we have also investigated the role of ATX- lysophosphatidic acid on the mineralization of isolated valves interstitial cells (VICs) and in a mouse model of CAVD. Enzyme specific ATX activity was elevated by 60% in mineralized aortic valves compared to control valves. Immunohistochemistry studies showed a high level of ATX in mineralized aortic valves, which co-localized with OxPL and apolipoprotein(a). We detected a high level of ATX activity in the Lp(a) fraction in circulation. Interaction between ATX and Lp(a) was confirmed by in situ proximity ligation assay. Moreover, we documented that VICs also expressed ATX in CAVD. We showed that ATX-lysophosphatidic acid promote the mineralization of the aortic valve through a NF-¿B/IL-6/BMP2 pathway. In LDLR-/-/ApoB100/100/IGFII mice, ATX is overexpressed and lysophosphatidic acid promotes a strong deposition of hydroxyapatite of calcium in aortic valve leaflets and accelerates the development of CAVD. Conclusions—ATX is transported in the aortic valve by Lp(a) and is also secreted by VICs. ATX-lysophosphatidic acid promotes inflammation and mineralization of the aortic valve and thus could represent novel therapeutic targets in CAVD.|
|Document Type:||Article de recherche|
|Issue Date:||25 August 2015|
|Open Access Date:||Restricted access|
|This document was published in:||Circulation, Vol. 132 (8), 677-690 (2015)|
American Heart Association, etc.
|Collection:||Articles publiés dans des revues avec comité de lecture|
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