Conditional over-expression of inducible nitric oxide synthase (iNOS) in cardiac and arterial myocytes of transgenic mice
Bibliographic record
Abstract
While nitric oxide gas (NO) and the endogenous constitutive NO-Synthase (NOS) enzymes are involved in the regulation of cardiac function and blood pressure, the specific effects of cardiovascular iNOS expression remain poorly defined. Interestingly, iNOS induction is a component of the immune response, and has been demonstrated in cardiac and arterial myocytes accompanying cardiovascular disease. To explore whether the consequences of such expression are adaptive or pathogenic, transgenic mice were generated conditionally targeting a human iNOS cDNA to either (a) myocardium or (b) vascular smooth muscle (SM). (a) Chronic cardiac-specific expression of iNOS in transgenic mice led to increased superoxide production, but no change in nitric oxide. In cardiomyocytes, this was associated with a mild inflammatory cell infiltrate, fibrosis, hypertrophy and dilatation. While iNOS over-expressing mice infrequently developed overt heart failure, they did not show decreased contractility. Interestingly, these mice displayed a high incidence of sudden cardiac death due to bradyarrhythmia, which was correlated with a down-regulation of Connexin 40 in the AV-node and major bundle branches. These data implicate cardiomyocyte iNOS over-expression as sufficient to cause bradyarrhythmia, cardiomyopathy and sudden cardiac death. (b) While there were no developmental or structural vascular defects, mice with chronic arterial SM iNOS over-expression had elevated blood pressure. Interestingly, temporal dissection of the hemodynamic effects due to arterial SM iNOS over-expression resulted in a biphasic response. Two weeks following transgene induction these mice had decreased blood pressure, while eight weeks or greater resulted in hypertension. Coincidental with the hypertensive phase, isolated mesenteric arteries from iNOS transgenic mice displayed normal development of myogenic tone, constrictions to phenylephrine and subsequent relaxations with sodium nitroprusside. However, hypertensive iNOS over-expressing mice had a dramatic impairment in acetylcholine dependent relaxation of pre-constricted mesenteric arteries. Since this dysfunction was reversed with tetrahydrobiopterin and L-arginine pre-treatment, a mechanism involving disruption of vascular endothelial eNOS substrate and cofactor balance is suggested. Collectively, these data are the first to implicate iNOS in the development of hypertension, and suggest the effects of arterial myocyte iNOS over-expression can modulate constitutive NOS via depletion of NOS substrates and co-factor.
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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) | 0.001 | 0.001 |
| Meta-epidemiology (broad) | 0.000 | 0.000 |
| Bibliometrics | 0.001 | 0.000 |
| Science and technology studies | 0.000 | 0.001 |
| Scholarly communication | 0.000 | 0.000 |
| Open science | 0.001 | 0.000 |
| Research integrity | 0.001 | 0.001 |
| Insufficient payload (model declined to judge) | 0.002 | 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".