Endothelial Pannexin 3 – B Cell Lymphoma‐6 Interactions Protect Against Oxidative Stress
Bibliographic record
Abstract
Pannexin channel isoforms (Panx1‐3) are thought to release nucleotides into the extracellular milieu and have been shown to effect vascular hemodynamics. For this reason, we examined their mRNA and protein expression in hypertensive humans and genetically‐inbred hypertensive mice. In both mouse and humans, we found a significant reduction in Panx3 expression in resistance artery endothelium. Thus, we hypothesized Panx3 may be a regulator of vascular function. In en face endothelial preparations from 3 rd order mesenteric arteries, we localized Panx3 to the Golgi Apparatus as opposed to Panx1 which localized to the plasma membrane. Next, we generated an inducible, endothelial cell Panx3 knockout mouse (Panx3 ECKO ). Radiotelemetry revealed a renin‐independent spontaneous hypertension, with unremarkable immune infiltration in the kidney. There was no change in cytoplasmic or released ATP. To understand how Panx3 may regulate blood pressure, we examined whether Panx3 interacted with B Cell Lymphoma 6 (BCL6), a potential binding partner. En face proximity ligation assays demonstrated an interaction between Panx3 and BCL6 in the Golgi. Panx3 ECKO mice exhibited significantly decreased BCL6 protein, hinting that Panx3 may stabilize BCL6 by binding at the BCL6 ubiquitin sites. In silico “threading” of the Panx3 sequence onto the cryo‐EM structure of Panx1 confirmed this site of interaction. BCL6 is a NFκB repressor, thus its degradation in Panx3 ECKO mice caused an increase in NFκB activity with IκBα and p100 significantly upregulated. A novel mimetic peptide designed to block Panx3‐BCL6 interactions was administered into C57Bl/6J mice, which recapitulated these results. In addition, Panx3 ECKO mice had increased endothelial NOX4 (but not NOX1 or NOX2), likely due to increased NFκB activity—this correlated with a significant increase in plasma H 2 O 2 , nitrotyrosine (NT3), and 4‐hydroxynonenal (4‐HNE). In line with this observation, 3rd order mesenteric arteries from Panx3 ECKO mice constricted (not dilated) to acetylcholine, which was rescued with the H 2 O 2 ‐scavenger catalase (1000U/mL), suggesting that vascular oxidative stress drives hypertension in Panx3 ECKO mice. Interestingly, Panx3 ECKO mice also exhibit a significant increase in IL‐4 receptors on endothelium, and increased IL‐4 cytokines in bone marrow lysates. Because IL‐4 can drive BCL6 expression in other cell types, we suggest a possible homeostatic immune‐endothelial signaling axis. These data elucidate a novel Golgi‐localized oxidative signaling pathway in endothelium with a potential immune‐derived negative feedback loop.
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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 | 0.000 | 0.000 |
| Open science | 0.000 | 0.000 |
| Research integrity | 0.000 | 0.001 |
| Insufficient payload (model declined to judge) | 0.002 | 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 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".