Abstract 13451: Oxldl-derived Lysophosphatidic Acid Generates a Nf-κB Signature Through Lpar1 That Promotes the Progression of Aortic Valve Stenosis

Abstract

Background: Mendelian randomization studies have revealed an association between low-density lipoprotein (LDL) and calcific aortic valve stenosis (CAVS). Circulating level of oxidized phospholipids, a component of oxidized LDL (OxLDL), is associated with the progression rate of CAVS. Autotaxin (ATX) is a lysophospholipase D enzyme that transforms lysophosphatidylcholine (LPC), into lysophosphatidic acid (LPA). Recently, we demonstrated that LPA, which is generated by ATX, was present in the aortic valve and was an important driver of aortic valve mineralization. However, the process whereby oxidatively transformed LDL promotes the development/progression of CAVS is largely unknown. Objective: We aimed to examine the molecular processes whereby OxLDL promotes the mineralization of the aortic valve and the progression of CAVS. Methods: We documented the expression of LPA receptor 1 (LPAR1) in explanted CAVS and in control non-mineralized aortic valves. Effects of OxLDL-LPA on osteoblastic differentiation of cultured valve interstitial cells (VICs) were investigated by using promoter luciferase assay and RT-qPCR analysis for the osteoblastic markers. Results: We found that autotaxin (ATX), a lysophospholipase D, is transported by the LDL fraction. Upon oxidation of LDL, LPA is generated through the activity of ATX, promoting a strong osteogenic activity in VICs. In-depth functional assays showed that OxLDL/LPA-mediated osteogenic activity in VICs relied on LPAR1 and phosphorylation of p65 on serine 536, which is recruited to the promoter of bone morphogenetic protein 2 ( BMP2 ). In human and mouse mineralized aortic valves, the expression of LPAR1 is increased. In obese diabetic LDLR -/- /ApoB 100/100 /IGFII transgenic mice (IGFII), the development of CAVS was associated with a rise of circulating LPA, which correlated with the plasma ATX activity and cholesterol level. In this murine model of an established CAVS, inhibition of LPAR1 with Ki16425 decreased the progression rate of CAVS by 3.0-fold. Conclusion: These findings indicate that OxLDL-mediated progression of CAVS is promoted by LPA driving an inflammatory pathway that promotes the osteogenic activity of VICs. LPAR1 may thus constitute a novel target to prevent the progression of CAVS.