Understanding intracellular angiotensin type I receptor function and interaction in rat cardiac fibroblasts
Bibliographic record
Abstract
G protein-coupled receptors (GPCRs) are a large family comprising 800 genes in humans. To date, multiple studies have localized angiotensin II (Ang II) type 1 and type 2 (AT1R and AT2R respectively), β-adrenergic, and endothelin receptors, as well as many other GPCR and growth factor receptors present on, and signaling from, endomembranes. In addition to their cell surface roles, AT1R and AT2R have been found on the nuclear membrane in cardiac cells. AT1R couples to both heterotrimeric Gq and β-arrestin1/2 but may also couple to other G proteins. AT2R is reported to couple with Gi and several reports indicate that it is important in AT1R antagonist-mediated cardioprotective treatment, suggesting signaling crosstalk between AT1R and AT2R. In isolated nuclei, the receptors couple to intranuclear calcium mobilization (AT1R) and nitric oxide (NO) production (AT2R). Nuclear AT1 (nAT1R) has been shown to impact cardiac fibroblast proliferation, the abundance of collagen transcripts, and type 1 collagen secretion. However, nuclear AT1R signaling remain poorly understood due the challenge of selectively targeting nuclear membrane receptors while avoiding their cell surface counterparts. We hypothesize that iAT1Rs elicit Gq/11- and β-arrestin-biased signaling resulting in the activation of different downstream effectors in cardiac fibroblasts (CFs). Using biased and unbiased caged intracellular AT1R (iAT1R) ligands, we report that myofibroblasts showed stronger transcriptional and secretory responses to iAT1R stimulation compared to quiescent fibroblasts. Additionally, quiescent atrial and ventricular fibroblasts showed lower collagen levels in conditioned media. In myofibroblasts, nAT1R stimulation led to lower calcium levels and β-arrestin biased nAT1R stimulation led to higher nuclear NO levels. Interestingly, we note that iAT1R stimulation increased detectable double stranded DNA breaks in ventricular myofibroblasts. Future work will aim to assess the full effect of iAT1R stimulation using RNA sequencing and to corroborate the data showing increases in DNA damage by measuring the cleaved to uncleaved caspase 3 ratios
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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 | 0.001 | 0.001 |
| Meta-epidemiology (narrow) | 0.001 | 0.001 |
| Meta-epidemiology (broad) | 0.001 | 0.000 |
| Bibliometrics | 0.001 | 0.001 |
| Science and technology studies | 0.001 | 0.000 |
| Scholarly communication | 0.000 | 0.000 |
| Open science | 0.000 | 0.000 |
| Research integrity | 0.001 | 0.002 |
| 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".