Angiotensin II signalling and calcineurin in cardiac fibroblasts: differential effects of calcineurin inhibitors FK506 and cyclosporine A
Bibliographic record
Abstract
INTRODUCTION: Cardiac remodelling is controlled by complex systems, including activation of the renin-angiotensin system (RAS) and signalling through MAP kinases and Ca2+-activated calcineurin. Whether Ang II, which increases [Ca2+]i and stimulates MAP kinases, mediates myocardial effects through calcineurin-dependent pathways remain unclear. We investigated effects of two calcineurin inhibitors, cyclosporine A (CsA) and tacrolimus (FK506) (10-10-10-6 mol/L, 20 mins) on activation of MAP kinases and on growth, pro-fibrotic and pro-inflammatory responses in Ang II-stimulated rat cardiac fibroblasts. METHODS AND RESULTS: Ang II increased phosphorylation of ERK1/2 and p38MAPK (1.5-1.8-fold, p<0.05) without effect on JNK. FK506, but not CsA, attenuated Ang II-stimulated MAP kinase activation. Molecular indices of cell growth (proliferating cell nuclear antigen (PCNA)), fibrosis (fibronectin, pro-collagen) and inflammation (iNOS), were upregulated by Ang II (12 hrs). FK506 and CsA inhibited PCNA effects. Ang II-induced pro-fibrotic and pro-inflammatory responses were inhibited by CsA. Ang II receptors, AT1R and AT2R, were not influenced by calcineurin inhibitors. Our data indicate differential calcineurin inhibitor sensitivity of MAP kinases and cellular responses in Ang II-stimulated fibroblasts. p38MAP kinase and ERK1/2 are regulated in a FK506-sensitive manner, whereas fibrosis and inflammation are CsA-sensitive. Cell proliferation is inhibited by both FKC506 and CsA. These are post-receptor phenomena, since AT1R and AT2R status was unaltered by treatment. CONCLUSIONS: Our findings identify an important role for calcineurin in MAP kinase/growth/pro-fibrotic/pro-inflammatory signalling by Ang II in cardiac fibroblasts. Although both FK506 and CsA inhibit calcineurin, they exert differential effects on molecular and cellular responses. Such differences may contribute to variable clinical responses of these agents.
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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 | 0.000 | 0.000 |
| Meta-epidemiology (narrow) | 0.000 | 0.000 |
| Meta-epidemiology (broad) | 0.001 | 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 | 0.000 |
| 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".