S-07-4: VASCULAR SMOOTH MUSCLE CELL PROTEOME AND PHENOTYPIC SWITCHING IN HUMAN HYPERTENSION ARE NOX5-DEPENDENT
Bibliographic record
Abstract
Objective: Reactive oxygen species (ROS) play a key role in the regulation of vascular smooth muscle cell (VSMC) phenotypic switching in hypertension. Nox5 is a major ROS-generating enzyme in vascular cells and is upregulated in hypertension. However, the effects of Nox5-derived ROS on VSMC proteome and phenotype in human hypertension are unknown. We aimed to characterize the global and oxidative proteomic profile and VSMC phenotype in human hypertension and the role of Nox5. Design and method: VSMC from resistance arteries from normotensive (NT) and hypertensive (HT) subjects were studied (n = 5). Proteins were labelled with isobaric tandem mass tags and identified by liquid chromatography tandem mass spectrometry. The oxidative proteome was assessed using stable isotope-labelled iodoacetamide to target cysteine thiols. Nox5 silencing was performed by siRNA. Protein expression was detected by western blotting. The inflammatory, pro-fibrotic and mitogenic phenotype of VSMCs was assessed by measuring pro-inflammatory cytokines (IL-6, IL-8), pro-collagen I in the culture media. Results: Proteomic analysis identified 207 proteins upregulated in HT subjects (fold change > 1.5, p < 0.05). Gene ontology enrichment analysis of upregulated proteins in HT showed most proteins belong to extracellular space and plasma membrane compartments and were involved in extracellular matrix organization (ECM), immune response and cell proliferation. ECM proteins COL1A1, COL9A1, COL10A1, FBN1, FBLN1 were increased in cells from HT, suggesting a switch to a fibroblast-like phenotype in hypertension. Expression of proteins related to interferon and IL-1β pathways (IFIT1, IFIT2, IFIT3, MX1, MX2, ABCA1, ABCA2, IL1RAP, CD36, ICAM1) were also increased in cells from HT subjects. The VSMC oxidative proteome analysis identified 130 significantly regulated cysteine-containing peptides, 88 showed increased oxidation in HT (fold change> 1.5, p < 0.05). Among the highly oxidized proteins in HT were ECM proteins, COL11A1, COL16A1, FBLN1 and FBLN2. VSMCs from HT subjects exhibit increased expression of the proliferation marker, PCNA (0.162 ± 0.3 vs NT:0.051 ± 0.04 relative fluorescence units, p < 0.05) and pro-collagen I (23.6 ± 2 vs NT:13.2 ± 0.3 ng/ml, p < 0.05). Production of pro-inflammatory cytokines IL-6 (501.8 ± 23.6 vs NT:121.7 ± 6.4 pg/mL) and IL-8 (373.6 ± 34.1 vs NT:262.5 ± 24.6 pg/mL, p < 0.05) were increased in HT. Nox5 silencing in VSMC from HT subjects reduced PCNA expression(43%), pro-collagen I release (8%), baseline and LPS-induced IL-6 (30% baseline, 43% LPS-induced) and IL-8 (21% baseline, 23% LPS-induced) release (p < 0.05). Conclusions: Our study provides new insights into the proteomic changes related to vascular phenotype in hypertension and demonstrated that Nox5 plays an important role in VSMC phenotypic switching associated with vascular injury and remodelling in hypertension.
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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 | 0.000 |
| Insufficient payload (model declined to judge) | 0.008 | 0.001 |
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".