Intracellular Angiotensin‐II Interacts With Nuclear Angiotensin Receptors in Cardiac Fibroblasts and Regulates RNA Synthesis, Cell Proliferation, and Collagen Secretion
Bibliographic record
Abstract
Background Cardiac fibroblasts play important functional and pathophysiological roles. Intracellular (“intracrine”) angiotensin‐ II (Ang‐ II ) signaling regulates intercellular communication, excitability, and gene expression in cardiomyocytes; however, the existence and role of intracrine Ang‐ II signaling in cardiac fibroblasts is unstudied. Here, we evaluated the localization of Ang‐ II receptors on atrial fibroblast nuclei and associated intracrine effects of potential functional significance. Methods and Results Immunoblots of subcellular protein‐fractions from isolated canine atrial fibroblasts indicated the presence of nuclear Ang‐II type 1 receptors ( AT 1Rs) and Ang‐II type 2 receptors ( AT 2Rs). Fluorescein isothiocyanate–Ang‐ II binding displaceable by AT 1R‐ and AT 2R‐blockers was present on isolated fibroblast nuclei. G‐protein subunits, including Gαq/11, Gαi/3, and Gβ, were observed in purified fibroblast nuclear fractions by immunoblotting and intact‐fibroblast nuclei by confocal immunocytofluorescence microscopy. Nuclear AT 1Rs and AT 2Rs regulated de novo RNA synthesis ([α 32 P] UTP incorporation) via IP 3R‐ and NO ‐dependent pathways, respectively. In intact cultured fibroblasts, intracellular Ang‐ II release by photolysis of a membrane‐permeable caged Ang‐ II analog led to IP 3R‐dependent nucleoplasmic Ca 2+ ‐liberation, with IP 3R3 being the predominant nuclear isoform. Intracellular Ang‐ II regulated fibroblast proliferation ([ 3 H]thymidine incorporation), collagen‐1A1 mRNA ‐expression, and collagen secretion. Intracellular Ang‐ II and nuclear AT 1R protein levels were significantly increased in a heart failure model in which atrial fibrosis underlies atrial fibrillation. Conclusions Fibroblast nuclei possess AT 1R and AT 2R binding sites that are coupled to intranuclear Ca 2+ ‐mobilization and NO liberation, respectively. Intracellular Ang‐ II signaling regulates fibroblast proliferation, collagen gene expression, and collagen secretion. Heart failure upregulates Ang‐ II intracrine signaling‐components in atrial fibroblasts. These results show for the first time that nuclear angiotensin‐ II receptor activation and intracrine Ang‐ II signaling control fibroblast function and may have pathophysiological significance.
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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 | 0.002 |
| 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".