AUTOTAXIN ENHANCES AORTIC VALVE MINERALIZATION THROUGH A NF-κB / IL-6 / BMP-2 DEPENDENT INFLAMMATORY PATHWAY

Abstract

Calcific aortic valve disease (CAVD) is characterized by a progressive mineralization of the aortic valve. Recent studies of Mendelian randomization have revealed an association between lipoprotein (a) [Lp (a)] and CAVD. However, the mechanism by which the Lp (a) causes aortic valve interstitial cells (VICs) calcification remains unknown. Lp (a) carries oxidized phospholipids (OxPLs) with a high content in lysophosphatidylcholine (LPC). The enzyme autotaxin (ATX) converts LPC into lysophosphatidic acid (LysoPA). We investigated whether ATX-produced LysoPA could induce mineralisation. We documented the expression of ATX in control and CAVD valves. We investigated in vitro the mechanisms by which ATX promotes inflammation and mineralization of VICs. These results were then validated in a mouse model of CAVD. In CAVD, immunohistochemical stainings revealed the expression of ATX by VICs and ATX co-distributed with Lp (a). Moreover, ATX-specific enzyme activity confirmed the expression of ATX in CAVD. An interaction between ATX and Lp (a) was revealed by 'proximity ligation assay'. Also, we have detected a high level of ATX activity in Lp (a) purified fractions. On the other hand, we showed that ATX promotes inflammation and mineralization of the aortic valve by the activation of a NF-kB / IL-6 / BMP-2 dependent pathway. LysoPA injections, in mice LDLR - / - / ApoB 100/100 / IGFII fed with a HFHS diet, accelerated the development of CAVD compared with HFHS diet alone. Echocardiographic analyzes of these mice showed a two fold increase in the delta velocity in comparison with control mice. ATX is transported in the aortic valve by Lp (a) and is secreted by VICs. ATX and LysoPA promote inflammation and mineralization of the aortic valve and could therefore represent new therapeutic targets in CAVD.