Abstract 262: Lipoprotein(a) Stimulates Pro-Inflammatory Phenotypes in Vascular Cells: Demonstration of a Role for the Lysine-Binding Properties of Apolipoprotein(a)
Bibliographic record
Abstract
Elevated plasma Lp(a) concentrations are a causal risk factor for a variety of atherosclerotic disorders. Although the role of Lp(a) in vascular disease remains poorly understood, the atherogenicity of Lp(a) may stem from the direct atherosclerotic effects of its LDL-like component, or from the presence of the unique protein component apolipoprotein(a) (apo(a)). It has been hypothesized that Lp(a) contributes to early atherogenesis by initiating a program of endothelial cell (EC) dysfunction which results in increased EC permeability and the adoption of a pro-coagulant and pro-inflammatory phenotype. In support of the latter, studies have shown that Lp(a) stimulates expression of cell adhesion molecules (CAMs) on ECs, and induces monocyte recruitment to these cells. In the present study we demonstrate that a recombinant 17 kringle form of apo(a) (17K) stimulates expression of CAMs on primary human umbilical vein endothelial cells (HUVECs) in both a time- and dose-dependent manner, as determined by qRT-PCR analysis. We found that 17K was able to induce the expression of ICAM1, E-Selectin, VCAM1, but not PE-CAM at pathophysiologically-relevant concentrations of apo(a). However, 17KD57A, lacking the strong lysine-binding site (sLBS) in KIV10, lacked these effects. 17K was also able to induce a dose dependant increase in ICAM1 expression in the THP-1 monocyte cell line, an effect that was completely abolished by the NF-B inhibitor BAY-11-7082. In a fluorescent monocyte adhesion assay, both Lp(a) and 17K apo(a) were able to stimulate increased monocyte adhesion to ECs. Using 17KD57A, we were able to show that this effect is dependent on the sLBS in KIV10. The presence of the sLBS in KIV10 has also been found to be required for the covalent oxidized phospholipid modification on apo(a). We report that multiple KIV10 sLBS mutants lack the oxPL modification, further supporting a pro-inflammatory role for an intact KIV10 domain. Taken together, these studies contribute to a more complete understanding of the pathophysiological role that the apo(a) component of Lp(a) plays in the initiation and progression of atherosclerosis, and has the potential to aid in the development new therapeutics aimed at reducing the harmful effects of Lp(a) in the vasculature.
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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 | 0.000 |
| Insufficient payload (model declined to judge) | 0.003 | 0.001 |
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".