SALT-INDUCED VASCULAR DYSFUNCTION INVOLVES REDOX ACTIVATION OF PARP/TRPM2 SIGNALLING AND INFLAMMASOME ASSEMBLY
Bibliographic record
Abstract
Objective: Many individuals with essential hypertension are salt sensitive. High salt diet (HSD) has deleterious effects on the vasculature by mechanisms not fully elucidated. We explored molecular mechanisms, focusing on pro-inflammatory pathways whereby HSD influences vascular function in hypertension focusing on PARP-regulated TRPM2, a redox-sensitive Ca2+ channel, and the inflammasome. In particular we assessed if HSD induces a pro-oxidant environment leading to PARP-induced TRPM2-activation, Ca2+ influx and inflammasome assembly, leading to vascular damage and hypertension. Design and method: C57BL/6 mice were treated with normal or 4% high salt diet (HSD) for 5 weeks. Vascular function/structure was assessed in mesenteric arteries mounted in wire/pressure myography. VSMCs from rodents and humans were exposed to normal (145 mM) and high salt medium (180 mM) (HSM). Results: In presence of HSM, VSMCs present increased ROS generation (Control:0.7033±0.05 vs HSM:1.243±0.09) and PARP activation (Control: 94.25±6.67 vs HSM: 369.6±79.46), effect no longer observed in presence of ROS scavenger tiron, and antioxidant PEG-catalase. HSM induces Ca2+ influx in VSMCs (Control: 25562±880.48 vs HSM: 30925±1263.85), effect reversed by tiron, PARP inhibitor (olaparib) and TRPM2 blocker (8-br). NLRP3 activation (IL-1beta and Il-18 production) in VSMCs is increased by HSM (IL18 - Control: 93.82±1.97 vs HSM:127.30±6.57; IL-1 beta Control: 99.86±2.49 vs HSM: 125.30±3.43) HSM, effect followed by myosin light chain phosphorylation, which is dependent on ROS, PARP and TRPM2 activation. Animals treated with HSD present increased systolic BP (Control: 121.3±2.15 vs HSD: 134.90±3.04), outward hypertrophic remodelling and increased vascular contractility, effect reversed by PARP and NLRP3 inhibitors. Conclusions: In conclusion, HSD-induced hypertension involves ROS generation leading to activation of PARP-TRPM2 axis, increased calcium influx, NLRP3 activation and consequent vascular hypercontractility. We define novel pathways linking HSD to pathophysiological mechanisms underlying salt-sensitive 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 | 0.001 |
| Bibliometrics | 0.000 | 0.000 |
| Science and technology studies | 0.000 | 0.000 |
| Scholarly communication | 0.000 | 0.001 |
| Open science | 0.000 | 0.000 |
| Research integrity | 0.001 | 0.001 |
| Insufficient payload (model declined to judge) | 0.003 | 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".