Abstract 428: Scavenger Receptor Class B Type I Is Required for Protection by High-Density Lipoprotein Against Doxorubicin-Induced Apoptosis in Both Mouse and Human Cardiomyocytes and Cardiotoxicity in Mice
Bibliographic record
Abstract
Doxorubicin (DOX) is a clinically used anti-tumor drug that induces cardiotoxicity. HDL protects against DOX induced apoptosis in isolated cardiomyocytes, though the pathways of protection are not well known. The scavenger receptor class B type I (SRBI) is a high affinity HDL receptor, and its absence in atherogenic mice leads to occlusive CAD and MI, though a direct role for SRBI in cardiomyocytes has yet to be studied. Here we utilized both in vitro cell culture and in vivo mouse models to assess whether SRBI is required for HDL induced protection against DOX induced cardiotoxicity. Mouse neonatal cardiomyocytes were isolated from C57Bl6 and SRBI KO hearts. SRBI was knocked down in SV40 immortalized human ventricular cardiomyocytes using siRNA. All cells were treated as follows: 24h lipoprotein starvation, 24h ±100μg/ml HDL, and 6h ±1μM DOX. Cells were then assessed for apoptosis. Secondly, male C57Bl6 or SRBI KO mice were injected i.p. with 5mg/kg DOX or saline by 5 weekly. Plasma was assessed for cardiac troponin-T. Heart sections were assessed for apoptosis and examined histologically. HDL protected against DOX-induced apoptosis in both C57Bl6 mouse cardiomyocytes (7.7±5.0 vs 23.7±1.8% apoptotic cardiomyocytes n=3 p<.05), and in immortalized human ventricular cardiomyocytes (6.7±2.1 vs 24.5±4.8% apoptotic cardiomyocytes n=3 p<.05). Conversely, HDL was unable to protect against DOX induced apoptosis in cardiomyocytes from SRBI KO mice (37.4±6.8 vs 35.5±8.3% apoptotic cardiomyocytes, n=3 p<.05), or immortalized human cardiomyocytes transfected with siSRBI (27.2±8.9 vs 31.3±3.7% apoptotic cardiomyocytes n=3 p<.05). In vivo studies showed that SR-BI KO hearts are more sensitive to DOX as shown by increased apoptosis (6.9±0.6 vs 3.9±0.7% apoptotic cardiomyocytes n=5/group p<.05) and greater plasma cardiac troponin T levels (1.7±0.3 vs 1.3±0.04ng/ml n=5/group p<.05). Hearts from DOX treated SRBI KO mice also exhibited greater myofibrillar loss, vacuolization, and inflammatory cell infiltration compared to C57Bl6 hearts. Our results indicate that SRBI mediates HDL induced protection in both mouse and human cardiomyocytes. We show here that SRBI is an important factor for the protection of the heart as a whole against DOX induced cardiotoxicity.
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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) | 0.007 | 0.003 |
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".