Abstract Tu0035: Lipoprotein(a) Induces a Proglycolytic and Proinflammatory Response in Coronary Artery and Aortic Valve Endothelial Cells, with Altered Metabolism and Reactive Oxygen Species Generation.
Bibliographic record
Abstract
Background: High plasma lipoprotein(a) (Lp(a)) is a risk factor for cardiovascular diseases including atherosclerosis and calcific aortic valve disease. The mechanisms by which Lp(a) acts remain to be clarified, however. Lp(a) elicits a proinflammatory phenotype in endothelial cells (ECs), with accompanying changes in metabolism towards glycolytic pathways. To further explore these mechanisms, and to compare the response of human coronary artery ECs (HCAEC) and human aortic valve ECs (HAVEC), we exposed these cells to purified Lp(a) in vitro and undertook transcriptomic and metabolic analyses. We hypothesize that Lp(a) induces a proinflammatory and oxidative stress response in ECs. Methods: Primary ECs were stimulated with 250 nmol/L Lp(a) or vehicle control for 2, 4, 8, and 16 hours (HCAEC) or 4, 8, and 16 hours (HAVEC). RNA was isolated, and global gene expression changes were examined by RNA-Seq (n=1). qRT-PCR was performed to validate Lp(a) effects on expression of selected genes. Additionally, the effect of Toll-like receptor (TLR) 2 and 4 and CD36 inhibition on Lp(a)-induced gene expression changes was assessed (n=3). Mitochondrial activity was measured by Seahorse assay, and ROS generation was quantified using commercially available assays. Results: RNA-seq analysis identified significant changes in HCAEC and HAVEC gene expression after Lp(a) treatment, with 1915 and 444 genes, respectively, identified as differentially expressed at 16 hours. KEGG pathway analysis showed significant (FDR < 0.05) enrichment in metabolic and proinflammatory signaling pathways, with distinct yet overlapping patterns in HCAEC and HAVEC. Interestingly, the most upregulated gene in both cell types was that encoding the stress response protein heme oxygenase-1 (HMOX-1), which was maximally induced by 50-fold in HCAEC and 7.5-fold in HAVEC. Moreover, Lp(a) increased mitochondrial activity, with a shift towards higher glycolysis, ROS generation, and ER stress in HCAEC. Lp(a)-induced expression of interleukin ( IL)1a and selectin ( SELE ), but not HMOX1 , was significantly (p<0.05) reduced with the inhibition of TLR2 and 4. Conclusions: The relationship between Lp(a) and HMOX-1, ROS and metabolic stress, as well as TLR-induced proinflammatory pathways, illuminates the mechanisms by which Lp(a) induces endothelial dysfunction in cardiovascular disease, creating pathways for the development of new disease prevention and management strategies.
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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 | 0.001 | 0.001 |
| Insufficient payload (model declined to judge) | 0.005 | 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".