Role of endothelin‐1, sodium hydrogen exchanger‐1 and mitogen activated protein kinase (MAPK) activation in glucose‐induced cardiomyocyte hypertrophy
Bibliographic record
Abstract
BACKGROUND: Cardiac hypertrophy is a key structural feature of diabetic cardiomyopathy. Previous studies have shown that diabetes-induced endothelin-1 (ET-1) and sodium hydrogen exchanger-1 (NHE-1) mediate structural and functional deficits in the heart. In order to gain a mechanistic understanding of the role of ET-1 and NHE-1 in cardiomyocyte hypertrophy, we have utilized an in vitro endothelial-myocyte co-culture system to reveal cellular interactions that may arbitrate cardiomyocyte deficits in diabetes. METHODS AND RESULTS: Rat ventricular cardiomyocytes were cultured in high glucose levels, which caused cellular hypertrophy. Hypertrophic markers, atrial natruritic peptide (ANP) and angiotensinogen (Agt), as well as inducible nitric oxide synthase (iNOS) were upregulated by high glucose. Treatment of cells with ET antagonist bosentan and NHE-1 inhibitor cariporide prevented glucose-induced cardiomyocyte hypertrophy and expression of ANP, Agt, and iNOS. Bosentan and cariporide treatment of cardiomyocytes co-cultured with endothelial cells produced a more pronounced normalization of glucose-induced changes as compared to cardiomyocyte cultured alone. To further explore the signaling mechanisms involved, we investigated the mitogen activated protein kinase (MAPK) pathway and its cross-interaction with signaling proteins known to be altered in diabetes. Our results indicate that MAPK activation is associated with cardiomyocyte hypertrophy and is inhibited by bosentan, cariporide, as well as protein kinase C inhibiton. Furthermore, MAPK activation was found to be upstream of the transcription factors, nuclear factor-kappaB and activating protein-1. CONCLUSION: These results demonstrate that ET-1 and NHE-1 may mediate cardiomyocyte hypertrophy via MAPK activation and provide an insight into the pathogenesis of diabetic cardiomyopathy.
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How this classification was reachedexpand
Full frame distilled prediction
Teacher imitationNot calibrated prevalence, not ground truth. Human validation pending. Learned from the 10,348 direct Codex labels and 10,348 direct Gemma labels. Candidate is the union of thresholded teacher heads; consensus is their intersection. These outputs are machine_predicted_unvalidated and are not human labels or direct frontier model labels.
Codex and Gemma teacher scores by category
| Category | Codex | Gemma |
|---|---|---|
| Metaresearch | 0.002 | 0.000 |
| Meta-epidemiology (narrow) | 0.000 | 0.000 |
| Meta-epidemiology (broad) | 0.001 | 0.000 |
| Bibliometrics | 0.001 | 0.001 |
| 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) | 0.000 | 0.000 |
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 teacher head, 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".