Abstract 215: Enhanced Atherosclerosis, Inflammation And Oxidized Phospholipid Reactivity In Female Transgenic Mice Expressing Human Lp(a)
Bibliographic record
Abstract
Despite increased clinical interest in the unique lipoprotein Lp(a), many questions remain about the molecular mechanisms by which it contributes to atherosclerotic cardiovascular disease. To address this knowledge gap we generated transgenic mice expressing both human apolipoprotein(a) (apo(a)) and human apoB100 (Tg(LPA +/0 ;APOB +/0 )), with pathogenic levels of plasma Lp(a) (mean 134 mg/dL; range 87–250 mg/dL). Female mice (n=12/group) were fed a high-fat, high-cholesterol diet and injected weekly with an antisense oligonucleotide targeting the Ldlr for 12 weeks to induce atherosclerosis. FPLC demonstrated that both Tg(LPA +/0 ;APOB +/0 ) and Tg(APOB +/0 ) mice exhibited proatherogenic lipoprotein profiles (increased cholesterol-rich VLDL and LDL-sized particles) and developed complex lesions in the aortic sinus. However, Oil Red O-staining reveled significantly increased plaque area (+23%) in Tg(LPA +/0 ;APOB +/0 ) mice, compared to Tg(APOB +/0 ) mice. Examination of lesion pathology indicated more severe disease in Tg(LPA +/0 ;APOB +/0 ) mice, with significantly increased necrotic core size (41.8±2.8% vs. 33.4±2.7%, (p<0.05)) and calcium deposition (2.96±0.3% vs. 1.79±0.4%, (p<0.05)). Furthermore, Picrosirius Red staining showed a significant, 1.2-fold increase in collagen abundance in lesions of Tg(LPA +/0 ;APOB +/0 ) vs. Tg(APOB +/0 ) mice. Immunohistochemistry on the lesions demonstrated that in Tg(LPA +/0 ;APOB +/0 ) mice, Lp(a) colocalized with apoB100, CD68-positive macrophages and E06/oxidized phospholipid (OxPL). Compared to Tg(APOB +/0 ) mice, quantitation of the E06/OxPL-positively stained area revealed a significant increase (+39%) in Tg(LPA +/0 ;APOB +/0 ) mice. Female Tg(LPA +/0 ;APOB +/0 ) mice also had a 2-fold increase in E06/OxPL apo(a) in plasma, as well as enhanced circulating levels of the proinflammatory cytokines TNFα (1.2-fold increase) and MCP-1 (2.8-fold increase) compared to Tg(APOB +/0 ) mice. Taken together these data suggest an exacerbated pro-inflammatory phenotype in female Tg(LPA +/0 ;APOB +/0 ) mice, potentially contributing to the development of more advanced lesions. Further study of this novel mouse model will aid in the understanding of the fundamental role of elevated Lp(a) in atherogenesis.
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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) | 0.001 | 0.000 |
| Meta-epidemiology (broad) | 0.000 | 0.000 |
| Bibliometrics | 0.001 | 0.000 |
| Science and technology studies | 0.000 | 0.001 |
| Scholarly communication | 0.001 | 0.000 |
| Open science | 0.000 | 0.000 |
| Research integrity | 0.001 | 0.001 |
| Insufficient payload (model declined to judge) | 0.005 | 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".