Bibliographic record
Abstract
Objective: We recently reported that activation of endocannabinoid receptors attenuates cardiac myocyte hypertrophy. Mitochondrial dysfunction has emerged as a critical determinant of aberrant myocyte energy production in cardiac hypertrophy. Thus, we determined endocannabinoid influence on mitochondrial function in the hypertrophied cardiac myocyte. Design and method: The experimental paradigm of hypertrophy in this study was neonatal rat cardiac myocytes treated with endothelin-1 (ET1; 0.1 μM). Ligand activation of cannabinoid receptors was achieved using CB13 (1 μM), a peripherally-restricted dual agonist of cannabinoid receptor subtypes CB1 and CB2. Changes in mitochondrial membrane potential (δψm) were assessed by fluorescence microscopy using the potential sensitive dye, JC-1. Biochemical modulators of mitochondrial function (i.e. peroxisome proliferator-activated receptor-γ coactivator 1α [PGC-1α - a driver of mitochondrial biogenesis], carnitine palmitoyl transferase 1β [CPT-1β - facilitator of fatty acid uptake], and AMP-activated protein kinase [AMPK – energy sensor]) were assessed by real-time PCR and western blotting. The Seahorse Bioscience XF24 Analyzer was used to measure fatty acid oxidation-related bioenergetics parameters. Results: ET1 caused mitochondrial aberrations which included membrane depolarization (δψm 80 ± 5% vs. control; p < 0.05), reduced PGC-1α (59 ± 7% vs. control; p < 0.01) and CPT-1β (81 ± 5% vs. control; p < 0.05) expression, as well as depressed palmitate-dependent respiration (basal/maximal/reserved respiration respectively: 81 ± 5%, 78 ± 4%, 74 ± 5% vs. control; p < 0.05), coupling efficiency (83 ± 6% vs. control; p < 0.05), and respiratory control ratio (79 ± 5% vs. control; p < 0.01). CB13 treatment restored all mitochondrial parameters to normal. Incidentally, CB13 activated AMPK via phosphorylation at Thr172 (354 ± 58% vs. control; p < 0.01), and the ability of CB13 to improve mitochondrial membrane potential and PGC-1α was abolished by compound C (a chemical inhibitor of AMPK) or shRNA knockdown of AMPK. These data suggest that AMPK contributes to the mitochondrial protective effects of CB13. Conclusions: The cardioprotective actions of liganded cannabinoid receptors extend to the mitochondrial level. Therefore, a cannabinoid-based treatment for cardiac disease remains a potential therapeutic strategy that warrants further study.
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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 | 0.001 | 0.002 |
| Meta-epidemiology (narrow) | 0.002 | 0.001 |
| Meta-epidemiology (broad) | 0.002 | 0.001 |
| Bibliometrics | 0.002 | 0.001 |
| Science and technology studies | 0.002 | 0.001 |
| Scholarly communication | 0.006 | 0.002 |
| Open science | 0.002 | 0.004 |
| Research integrity | 0.004 | 0.002 |
| Insufficient payload (model declined to judge) | 0.926 | 0.921 |
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".