Autotaxin and Lipoprotein Metabolism in Calcific Aortic Valve Disease

Abstract

Calcific aortic valve disease (CAVD) is a complex trait disorder characterized by calcific remodeling of leaflets. Genome-wide association (GWA) study and Mendelian randomization (MR) have highlighted that LPA, which encodes for apolipoprotein(a) [apo(a)], is causally associated with CAVD. Apo(a) is the protein component of Lp(a), a LDL-like particle, which transports oxidized phospholipids (OxPLs). Autotaxin (ATX), which is encoded by ENPP2, is a member of the ecto-nucleotidase family of enzymes, which is, however, a lysophospholipase. As such, ATX converts phospholipids into lysophosphatidic acid (LysoPA), a metabolite with potent and diverse biological properties. Studies have recently underlined that ATX is enriched in the Lp(a) lipid fraction. Functional experiments and data obtained in mouse models suggest that ATX mediates inflammation and mineralization of the aortic valve. Recent findings also indicate that epigenetically-driven processes lower the expression of phospholipid phosphatase 3 (PLPP3) and increased LysoPA signaling and inflammation in the aortic valve during CAVD. These recent data thus provide novel insights about how lipoproteins mediate the development of CAVD. Herein, we review the implication of lipoproteins in CAVD and examine the role of ATX in promoting the osteogenic transition of valve interstitial cells (VICs).

Keywords: aortic valve; autotaxin (ATX); calcific aortic stenosis; inflammation; phospholipid (PL).

Figure 1

Circulating Lp(a) particles associate with ATX and enter the aortic valve, where ATX can metabolize lysophosphatidylcholine (LysoPC) presents in the Lp(a) particles into lysophosphatidic acid (LysoPA). Pericellular LysoPA can then associate with LPAR1, which promotes NF-κB nuclear translocation. NF-κB activation results in elevated expression of the IL-6 and BMP-2 pro-osteogenic factors. ATX, autotaxin; LPAR1, lysophosphatidic acid receptor 1; IL-6, interleukin 6; BMP2, bone morphogenetic protein 2; NF-κB, nuclear factor kappa B.

Figure 2

DNA methylation and H3K27 trimethylation in intronic enhancer results in decreased PLPP3 expression and leads to increased LysoPA level, which promotes osteogenic signaling (With permission from Mkannez et al. (55). EED, embryonic ectoderm development; SUZ12, SUZ12, polycomb repressive complex 2 subunit; EZH2, enhancer of zeste 2 polycomb repressive complex 2 subunit; DNMT3, DNA methyltransferase 3 like.