Abstract 514: Treatment of Mice with ApoA1 Protects Them Against Doxorubicin Induced Cardiotoxicity in a Scavenger Receptor Class B Type I Dependent Manner
Bibliographic record
Abstract
Doxorubicin (DOX), a widely used chemotherapeutic agent, is associated with acute cardiotoxicity and long term development of congestive heart failure. DOX induces cardiomyocyte apoptosis leading to a progressive reduction in cardiac function over time. We recently showed that transgenic overexpression of human apolipoprotein A1 (apoA1), the major apolipoprotein component of HDL, protected mice against DOX-induced myocardial apoptosis. Here we tested if the pharmacologic treatment of mice with purified human apoA1 protein affected DOX induced cardiotoxicity and cardiac dysfunction. To examine acute DOX cardiotoxicity, mice were injected with a single, high DOX dose (10 mg/kg body weight) and myocardial apoptosis was evaluated by TUNEL staining in histological sections of hearts 1 wk later. To examine longer term effects of DOX on cardiac function, in a separate experiment, mice were treated once weekly with a lower DOX dose (5 mg/kg body weight) for 5 weeks and left ventricular (LV) function was assessed by invasive hemodynamics. In each case one cohort of mice was injected with purified human apoA1 (14 mg/kg body weight) 3 hrs before and 5 hrs after each DOX treatment. Control mice were treated either with saline instead of apoA1 or instead of both apoA1 and DOX. Treatment of mice with apoA1 dramatically reduced DOX induced myocardial apoptosis when evaluated 1 wk after treatment with a single DOX dose. DOX treatment for 5 wks dramatically reduced LV function when assessed by pressure-volume loop analysis. ApoA1 treatment, however, protected mice against DOX induced LV dysfunction. Furthermore, pre-treatment of isolated neonatal cardiomyocytes from wild type mice with HDL protected them against DOX-induced apoptosis. This protection was lost the HDL receptor, SR-B1, was absent. Similarly apoA1 treatment failed to protect SR-B1 deficient mice from DOX-induced myocardial apoptosis LV dysfunction. In conclusion, our results suggest that HDL-based therapy has the potential to protect against DOX-induced cardiotoxicity and cardiac dysfunction in a manner mediated by SR-B1.
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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) | 0.001 | 0.001 |
| Bibliometrics | 0.001 | 0.000 |
| Science and technology studies | 0.000 | 0.001 |
| Scholarly communication | 0.000 | 0.001 |
| Open science | 0.000 | 0.000 |
| Research integrity | 0.001 | 0.002 |
| 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".