Abstract 13451: Oxldl-derived Lysophosphatidic Acid Generates a Nf-κB Signature Through Lpar1 That Promotes the Progression of Aortic Valve Stenosis
Bibliographic record
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.
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How this classification was reachedexpand
Full frame machine prediction
Teacher imitationNot calibrated prevalence, not ground truth. Human validation pending. The Gemma side is a direct model label for every work in the frame, read from the title-only record. The Codex side is a classifier learned from the 10,348 direct Codex labels and calibrated to design-weighted sample rates; fields without enough sample support carry no Codex call. Candidate is the union of the two sides; consensus is their intersection. These outputs are machine_predicted_unvalidated and are not human labels.
Distilled classifier scores by category (both heads)
| Category | Codex | Gemma |
|---|---|---|
| Metaresearch | 0.000 | 0.000 |
| Meta-epidemiology (narrow) | 0.000 | 0.000 |
| Meta-epidemiology (broad) | 0.000 | 0.000 |
| Bibliometrics | 0.000 | 0.000 |
| Science and technology studies | 0.000 | 0.000 |
| Scholarly communication | 0.000 | 0.000 |
| Open science | 0.000 | 0.000 |
| Research integrity | 0.000 | 0.001 |
| Insufficient payload (model declined to judge) | 0.010 | 0.002 |
Machine scores (provisional)
The two teacher heads of the student model, read on this work. A score orders the frame for review; it never asserts a category, and the validation status ships verbatim with every row.
Baseline scores from an immature model (maturity gate not passed, 7 training rounds). Scores rank; they never assert a category.
score_only:v0-immature-baseline · verbatim from the scoring run: score_only means the number may rank works, and no category label ships from itClassification
machine, unvalidatedMachine predicted; a candidate call from one source (direct Gemma or distilled Codex), not a consensus.
How this classification was reached, model by model and score by score, is at the end of the page under "How this classification was reached".