Abstract 18: Increasing in vivo Apoa1/HDL Levels Negates the Cardiotoxic Effects of Doxorubicin, and Involves Signalling Through SR-BI, PI3K, and AKT1
Bibliographic record
Abstract
Doxorubicin (DOX) is a clinically used anti-tumor drug, though the use of DOX is limited by its potent cardiotoxic side effect that can lead to heart failure. HDL protects isolated cardiomyocytes against DOX induced apoptosis, though whether this effect translates in vivo has yet to be determined. Here we assess whether ApoA1/HDL overexpression can protect mice in vivo against DOX induced cardiotoxicity, and explore the intracellular signalling mechanisms involved in protection. Mice overexpressing human ApoA1 (ApoA1tg/tg) and ApoA1+/+ mice were treated chronically with DOX, and effects on cardiac function and cardiomyocyte health were assessed. Over expression of human ApoA1 in mice corresponded to ~2.5 fold increase in plasma HDL-C as compared to ApoA1+/+ mice. Following 5 weekly injections of 5mg/kg DOX, ApoA1+/+ mice displayed cardiac dysfunction as evidenced by reduced left ventricular developed pressure, and reduced rate of pressure development. In contrast, left ventricular function was maintained following DOX treatment in ApoA1tg/tg mice. Histological analysis revealed reduced cardiomyocyte cross-sectional area and increased cardiomyocyte apoptosis following DOX treatment in ApoA1+/+ mice. ApoA1tg/tg mice, on the other hand, were protected against DOX induced cardiomyocyte atrophy and apoptosis. Interestingly, pAKT:tAKT was reduced in ApoA1+/+ by treatment with DOX, but the ratio was maintained in ApoA1tg/tg mice. We evaluated the roles of SR-BI, PI3K, and AKT1/2 in the signalling cascade of HDL in neonatal mouse cardiomyocytes and human immortalized ventricular cardiomyocytes. Through inhibition of AKT and PI3K, and knockdown or knockout of SR-BI, AKT1, and AKT2, we demonstrated that SR-BI, PI3K and AKT1 are required for HDL mediated protection against DOX induced cardiomyocyte apoptosis. Our results provide evidence for ApoA1 mediated protection against DOX cardiotoxicity in vivo and demonstrate the roles of SR-BI, PI3K, and AKT1 as mediators in the protective effect.
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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) | 0.005 | 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".