Autotaxin Derived From Lipoprotein(a) and Valve Interstitial Cells Promotes Inflammation and Mineralization of the Aortic Valve

Abstract

The main process that triggers pathological mineralization of the aortic valve remains elusive. 3 Recently, 3 successive studies with a Mendelian randomization design have reported a significant association between the LPA gene variant (rs10455872), which genetically determines the lipoprotein(a) [Lp(a)] plasma level, and CAVD. [4][5][6] These studies thus suggested a causal relationship between Lp(a) and CAVD risk. Lp(a) is a low-density lipoprotein (LDL)-like particle in which an apolipoprotein(a) is linked by a disulfide bridge to apolipoprotein B. Lp(a) is a major carrier of oxidized phospholipids (OxPLs) and has been associated Background-Mendelian randomization studies have highlighted that lipoprotein(a) [Lp(a)] was associated with calcific aortic valve disease (CAVD). Lp(a) transports oxidized phospholipids with a high content in lysophosphatidylcholine. Autotaxin (ATX) transforms lysophosphatidylcholine into lysophosphatidic acid. We hypothesized that ATXlysophosphatidic 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 in the mineralization of isolated valve interstitial cells and in a mouse model of CAVD. Enzyme-specific ATX activity was elevated by 60% in mineralized aortic valves in comparison with control valves. Immunohistochemistry studies showed a high level of ATX in mineralized aortic valves, which colocalized with oxidized phospholipids 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 valve interstitial cells also expressed ATX in CAVD. We showed that ATX-lysophosphatidic acid promotes the mineralization of the aortic valve through a nuclear factor κB/interleukin 6/bone morphogenetic protein pathway. In LDLR -/-/ApoB 100/100 /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

ApoB/ApoA‐I Ratio is Associated With Faster Hemodynamic Progression of Aortic Stenosis: Results From the PROGRESSA (Metabolic Determinants of the Progression of Aortic Stenosis) Study

“…Therefore, this lipid accumulation and retention, may act as a “warning” signal triggering the pathophysiologic processes involved in the development and progression of AS 4, 37. To this effect, autotaxin transported by lipoproteins promotes the production of lysophosphatidic acid, a lipid metabolite that drives inflammation and an osteogenic program in the aortic valve 38, 39. An increased apoB/apoA‐I ratio may also be a marker for small, dense lipoprotein particles 29, 40, 41.…”

Lipoprotein (a) in calcific aortic valve disease: from genomics to novel drug target for aortic stenosis

“…Importantly, TLR-4 is expressed at much higher levels on leftsided valves and may explain, in addition to the higher hemodynamic stress, the increased predilection for OxPLs to induce AV calcification (51). Recently, Bouchareb et al (52) have also implicated autotaxin (ATX) in Lp(a)-mediated calcification. ATX activity was 60% higher in calcified AVs than controls and colocalized with OxPLs and apo(a).…”

Reduction in lipoprotein-associated apoC-III levels following volanesorsen therapy: phase 2 randomized trial results

“…Lp(a) is now accepted as a causal independent genetic risk factor for CVD ( 26,27 ) and for aortic stenosis (28)(29)(30)(31). Lp(a) has multiple mechanisms leading to atherogenicity and infl ammation, including its content of pro-infl ammatory oxidized phospholipids (32)(33)(34)(35).…”