Salt-Induced Vascular Damage in Hypertension Involves Redox Activation of PARP/TRPM2 Signaling and Inflammasome Assembly
Bibliographic record
Abstract
BACKGROUND: Excess sodium intake induces vascular dysfunction. Molecular mechanisms underlying this are unclear. Here we investigated the role of reactive oxygen species (ROS), Ca2+ signaling and inflammation in salt-induced vascular injury, focusing on the interplay between redox-sensitive Poly(ADP-ribose) polymerase (PARP), which activates transient receptor potential melastatin 2 (TRPM2) Ca2+ channel, and nucleotide-binding oligomerization domain-like receptor protein 3 (NLRP3) inflammasome. Specifically, we sought to determine if salt excess induces a pro-oxidant environment, leading to PARP-induced TRPM2 activation and increased Ca2+ influx, inflammasome assembly, and consequent vascular damage. METHODS: Vascular smooth muscle cells (VSMCs) from rats and humans were exposed to normal NaCl (140 mM) and high-salt conditions (180 mM). RESULTS: High salt increased ROS generation, PARP activation, and TRPM2-mediated Ca2+ transients. Osmotic controls had no effect on these processes. High-salt medium promoted the release of pro-inflammatory cytokines interleukin-18 and interleukin-1β and increased phosphorylation of myosin light chain (MLC) in VSMCs. These effects were attenuated by inhibitors of PARP (Olaparib), TRPM2 (8-Br-cADPR), and NLRP3 inflammasome (MCC950). To validate these findings in in vivo, mice were subjected to a high-salt diet (4% NaCl, 5 weeks), resulting in elevated blood pressure and vascular remodeling and dysfunction. Exposure of vessels to olaparib and MCC950 attenuated the hypercontractility associated with a high-salt diet. CONCLUSIONS: Salt-induced vascular injury in hypertension involves ROS generation in VSMCs leading to activation of the PARP/TRPM2 axis, increased Ca2+ influx, NLRP3 activation, and vascular injury. Our study provides new insights into molecular pathways involved in high-salt diet-induced vascular dysfunction, important in hypertension.
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How this classification was reachedexpand
Full frame distilled prediction
Teacher imitationNot calibrated prevalence, not ground truth. Human validation pending. Learned from the 10,348 direct Codex labels and 10,348 direct Gemma labels. Candidate is the union of thresholded teacher heads; consensus is their intersection. These outputs are machine_predicted_unvalidated and are not human labels or direct frontier model labels.
Codex and Gemma teacher scores by category
| Category | Codex | Gemma |
|---|---|---|
| Metaresearch | 0.001 | 0.001 |
| Meta-epidemiology (narrow) | 0.000 | 0.000 |
| Meta-epidemiology (broad) | 0.001 | 0.000 |
| Bibliometrics | 0.001 | 0.001 |
| 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) | 0.000 | 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 teacher head, 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".