Inhibition of Endothelial Nitric Oxide Synthase by C-Reactive Protein: Clinical Relevance
Bibliographic record
Abstract
In 2002, 2 groups independently reported that C-reactive protein (CRP) inhibits endothelial nitric oxide synthase (eNOS) activity and bioactivity (1)(2). There was much reported debate as to whether these effects were artifacts attributable to CRP contamination with azide and endotoxin. In cells in which the endotoxin receptor Toll-like receptor 4 was knocked down by use of the small-interfering RNA technique, investigators convincingly showed that extensively dialyzed solutions of CRP inhibited eNOS, confirming that this inhibition was not an effect of endotoxin or azide(3). In a subsequent study, the molecular mechanism by which CRP inhibits eNOS was elucidated(4). This study demonstrated that CRP inhibited GTP cyclohydrolase 1 and stimulated NADPH oxidase, causing a decrease in tetrahydrobiopterin and an increase in reactive oxygen species, resulting in uncoupling of eNOS, which led to decreased eNOS activity, decreased phosphorylation of Ser1177 of eNOS, and decreased eNOS binding to Hsp90. Other investigators had shown that CRP also impairs vasoreactivity in vivo. In particular, Mineo and coworkers demonstrated in C57BL mice that intraperitoneal administration of CRP (250 μg) compared to administration of a vehicle control impaired acetylcholine-induced carotid artery vascular conductance by 50%, but no mechanistic insights were provided(5). Until the results of these 2 studies were reported, it had not been appreciated that endotoxin stimulates eNOS whereas CRP inhibits eNOS(4)(5). In 2007, Schwedler and coworkers (6) showed that subcutaneous administration of CRP for 8 weeks induced endothelial dysfunction in apolipoprotein E−/− mice, and that this effect was reversed with an inducible NOS inhibitor(6). However, these …
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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 | 0.011 |
| Meta-epidemiology (narrow) | 0.001 | 0.001 |
| Meta-epidemiology (broad) | 0.002 | 0.001 |
| Bibliometrics | 0.000 | 0.000 |
| Science and technology studies | 0.000 | 0.001 |
| Scholarly communication | 0.000 | 0.000 |
| Open science | 0.000 | 0.000 |
| Research integrity | 0.004 | 0.007 |
| 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; both teacher heads agree on what is shown here.
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".