UCMS Causes Indiscriminate Impairment of Aortic Function in Both Lean and Obese Rats, Mediated Through a TNFα and NOX2 Dependent Pathway
Notice bibliographique
Résumé
The use of unpredictable chronic mild stress (UCMS) protocols to cause stress leading to the onset of depressive like symptoms is well defined. Many studies have investigated the impact on behavior and neuronal functioning but its effect on vascular function is not well understood. Additionally, the combination of a depressive like state and metabolic syndrome (MetS) may further worsen the severity of vascular dysfunction, which is of high clinical relevance due to a high co‐prevalence. Similarly to MetS, chronic stress (UCMS) induces increases in oxidative stress, inflammation, and vascular dysfunction. Chronic stress also triggers increased sympathetic outflow and cortisol/corticosterone levels. All of these conditions can lead to impairment of endothelial function of the aorta. We have previously shown MetS impairment of aortic function is mediated, a least partially, through perivascular adipose tissue (PVAT). Adipose immune cells may play a big role in this impairment as they infiltrate the PVAT. These immune cells have the NADPH oxidase 2 (NOX2) enzyme that produces superoxides, contributing to higher oxidative stress. From previous data we know TNFαa neutralization blocks the MetS PVAT impairment and TNFα can stimulate NOX2 to produce of superoxides, which can be converted to hydrogen peroxide a more stable radical with more far reaching effects. The oxidative environment intern promotes the production of inflammatory mediators like TNFα. This highlights the interplay between inflammation and oxidative stress. The object of the current experiment was to determine the effect of UCMS with and without concomitant MetS on PVAT and PVAT regulation of aortic function. In lean rats (LZR) UCMS causes minimal effect to aortic relaxation, however relaxation (71% to 63%, p<0.05) and NO production (~40%) are impaired in the presence of PVAT. UCMS impairments appear to be caused by increased NOX2 superoxide production in PVAT and increased levels of TNFα as neutralizing TNFα or inhibiting the NOX2 enzyme resolved the PVAT mediated impairment of aortic relaxation. MetS (obese Zucker rat, OZR) alone causes significant aortic dysfunction mediated by PVAT (10% reduction of relaxation, p<0.05), which is further impaired (an additional 8%, p<0.05) by UCMS concurrent with MetS. Aortic relaxation was impaired by both, reducing sensitivity of relaxation at low doses of methacholine and reduced maximal relaxation from 64% to 50% mediated by the effect of PVAT on aortic NO production. OZR UCMS PVAT caused a significant drop in NO production below the non‐stimulated control suggesting severe endothelial dysfunction. Superoxide production (via DHE assay) was elevated in OZR UCMS. Similar to LZR, neutralizing TNFα or inhibiting the NOX2 enzyme resolved the PVAT mediated impairment. In summary UCMS causes increased superoxide production from NOX2 accompanied by increased TNFα in the PVAT. This led to impairment of aortic endothelial NO production and reduced aortic relaxation in both LZR and OZR. Support or Funding Information The authors gratefully acknowledge the support by National Institute of Health(5P20GM109098) and American Heart Association pre‐Doctoral Fellowship.
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Prédiction distillée sur la base complète
Imitation des enseignantsNi prévalence calibrée, ni vérité terrain. Validation humaine à venir. Apprise à partir de 10 348 étiquettes directes de Codex et de 10 348 étiquettes directes de Gemma. Le mode candidate est l'union des têtes enseignantes seuillées; le consensus est leur intersection. Ces sorties portent le statut machine_predicted_unvalidated et ne sont ni des étiquettes humaines ni des étiquettes directes de modèles de pointe.
Scores Codex et Gemma par catégorie
| Catégorie | Codex | Gemma |
|---|---|---|
| Métarecherche | 0,001 | 0,000 |
| Méta-épidémiologie (sens strict) | 0,000 | 0,000 |
| Méta-épidémiologie (sens large) | 0,000 | 0,000 |
| Bibliométrie | 0,000 | 0,000 |
| Études des sciences et des technologies | 0,000 | 0,000 |
| Communication savante | 0,000 | 0,000 |
| Science ouverte | 0,000 | 0,000 |
| Intégrité de la recherche | 0,000 | 0,000 |
| Charge utile insuffisante (le modèle a refusé de juger) | 0,000 | 0,000 |
Scores machine (provisoires)
Les deux têtes enseignantes du modèle étudiant, lues sur ce travail. Un score ordonne la base pour la relecture; il n'affirme jamais une catégorie, et le statut de validation accompagne chaque rangée tel quel.
Scores de référence d'un modèle non mature (critères de maturité non atteints, 7 itérations). Un score ordonne; il n'affirme jamais une catégorie.
score_only:v0-immature-baseline · tel quel depuis la passe de notation : score_only signifie que le nombre peut ordonner les travaux, et qu'aucune étiquette de catégorie n'en découleClassification
machine, non validéePrédiction automatique; un appel candidat d’une seule tête enseignante, pas un consensus.
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