A10817 Nox5 regulation of vascular contraction involves oxidation of endoplasmic reticulum calcium channels and calreticulin
Bibliographic record
Abstract
Objectives: The function of calcium-sensitive Nox5 is unknown. Considering the importance of calcium and ROS in the regulation of vascular function we questioned whether Nox5 plays a role in vascular contraction. Methods: Human arteries and mice expressing human Nox5 in smooth muscle (Nox5+SM22+) were studied and used for VSMC culture. Results: In arteries from hypertensive subjects, Nox5 expression, assessed by immunoblotting, was increased (50%, p < 0.05 vs control). In human VSMCs, AngII-induced ROS generation (1 fold) and activation of myosin light chain (MLC) (2.5 fold) were exacerbated in hypertension (p < 0.05 vs control); an effect blocked by Nox5 siRNA. Contraction to U46619 was increased in Nox5+/SM22+ (5.8 ± 0.3 mN vs WT: 4.2 ± 0.2 mN, p < 0.05). This was blocked by a NAC (ROS scavenger), calmidazolium (calmodulin inhibitor), dantrolene (ryanodine receptor Ca2+ channel inhibitors) and CDN1163 (SERCA activator), but not by a Nox1/Nox4 inhibitor (GKT137831). ONOO- levels were increased in vessels from Nox5+/SM22+ (5.8 ± 1 vs WT 3.4 ± 0.1 AU/mg, p < 0.05). Inactivation of MYPT1 (181 ± 1.8AU vs 164 ± 1.9AU WT) and activation of MLC (207 ± 10.3AU vs 155 ± 2.7AU WT) were increased in VSMC from Nox5+SM22+ (p < 0.05). In VSMCs from Nox5+SM22+ where reversibly oxidized proteins were immunoprecipitated, we observed oxidation of Nox5, decreased oxidation of MYPT1 and increased oxidation of SERCA2b. Proteome analysis of human VSMCs identified the ER Ca2+ sensor, calreticulin, as a potential Nox5 binding protein. Reversible oxidation of calreticulin was increased in VSMCs from Nox5+SM22+ mice and hypertensive subjects. Conclusion: Our study unravels crosstalk between redox signalling and Ca2+ in the vasculature, where Nox5 regulation of contraction is dependent of ROS, Ca2+ and endoplasmic reticulum localized Ca2+ channels/proteins.
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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 | 0.001 |
| 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 | 0.001 | 0.001 |
| Insufficient payload (model declined to judge) | 0.010 | 0.002 |
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".