Abstract 1360: A Potential Role for Nuclear-Delimited Signaling via Nuclear-Envelope Angiotensin Receptors in the Control of Cardiac Gene Expression
Bibliographic record
Abstract
Angiotensin-II (A-II) regulates cardiac homeostasis via AT1 (AT1R) and AT2 (AT2R) receptors. A-II mitogenic and growth promoting effects contribute to various cardiac remodeling paradigms, largely by altering gene expression. Here, we assessed the possibility that A-II effects on gene expression may be mediated by intracellular A-II acting on AT1Rs or AT2Rs in the nuclear envelope. Western blots of nucleus-enriched rat heart fractions indicated the presence of AT1R and AT2R proteins that preferentially copurified with a nuclear-membrane marker (Nup 62) but not markers of plasma (Calpactin I), Golgi (GM130) or endoplasmic-reticulum (GRP78) membranes. Confocal immunoflorescent microscopy of adult rat and dog cardiomyocytes revealed AT1R and AT2R proteins on nuclear membranes and T tubules. Microinjection of AngII-Alexa488 into single cardiomyocytes indicated preferential binding of A-II to nuclear vs cytoplasmic sites (197 ± 7* vs 110 ± 7 respectively; *p<0.05). Ca 2+ i -recordings on nuclear preparations (Fura-2 AM) revealed AT1R-mediated Ca 2 + release (e.g. 17 ± 2 nM control, 264 ± 13 nM* Ang-II and 177±6 nM* for the AT1-selective agonist L-162313). AT1R ligands enhanced de novo RNA synthesis in isolated cardiac nuclei incubated with [ α 32 P]-UTP (eg 45±1 CPM/ng DNA control vs 244±3 CPM/ng DNA* with A-II, N=6/group, P<0.001). NF κ B mRNA expression (RT-qPCR, relative to β -actin) was enhanced by A-II or L-162313 applied to isolated cardiac nuclei, a response that was suppressed by co-administration of valsartan (AT1-selective antagonist). Dose-response experiments with A-II applied to purified nuclei vs whole myocytes showed a 1.5-fold* greater increase in NF κ B mRNA levels at saturating concentrations with similar EC50 values, suggesting preferential nuclear signaling. Cardiac nuclear membranes possess AT2Rs and AT1Rs that are coupled to nuclear signaling pathways and regulate transcription. Intracellularly synthesized A-II signaling through cardiac nuclear envelopes may be particularly important for A-II regulation of cardiac gene expression, suggesting potential differential actions of A-II from intra- vs extracellular sources, with important mechanistic and therapeutic implications.
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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 | 0.000 | 0.000 |
| Meta-epidemiology (narrow) | 0.000 | 0.000 |
| Meta-epidemiology (broad) | 0.000 | 0.000 |
| Bibliometrics | 0.000 | 0.000 |
| Science and technology studies | 0.000 | 0.000 |
| Scholarly communication | 0.001 | 0.000 |
| Open science | 0.000 | 0.000 |
| Research integrity | 0.000 | 0.001 |
| Insufficient payload (model declined to judge) | 0.011 | 0.003 |
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".