Betulinic acid attenuates lipopolysaccharide-induced vascular hyporeactivity in the rat aorta by modulating Nrf2 antioxidative function.
Animals
Antioxidants
/ metabolism
Aorta, Thoracic
/ drug effects
Glutathione
/ metabolism
Interleukin-1beta
/ metabolism
Lipopolysaccharides
/ pharmacology
Male
Malondialdehyde
/ metabolism
NF-E2-Related Factor 2
/ metabolism
NF-kappa B
/ metabolism
Nitric Oxide
/ metabolism
Oxidative Stress
/ drug effects
Pentacyclic Triterpenes
Rats
Rats, Sprague-Dawley
Superoxide Dismutase
/ metabolism
Triterpenes
/ pharmacology
Tumor Necrosis Factor-alpha
/ metabolism
Betulinic Acid
Betulinic acid
Lipopolysaccharide
Nrf2
Oxidative stress
Vascular hyporeactivity
Journal
Inflammopharmacology
ISSN: 1568-5608
Titre abrégé: Inflammopharmacology
Pays: Switzerland
ID NLM: 9112626
Informations de publication
Date de publication:
Feb 2020
Feb 2020
Historique:
received:
24
02
2019
accepted:
17
07
2019
pubmed:
29
7
2019
medline:
18
11
2020
entrez:
29
7
2019
Statut:
ppublish
Résumé
Betulinic acid (BA), a pentacyclic triterpenoid, has been reported to inhibit cardiovascular dysfunction under sepsis-induced oxidative stress. Nuclear factor erythroid-2 related factor-2 (Nrf2) is regarded as a key transcription factor regulating expression of endogenous antioxidative genes. To explore the preventive effects of BA against vascular hyporeactivity and the related antioxidative mechanism in sepsis, contraction and relaxation in aortas isolated from lipopolysaccharide (LPS)-challenged rats were performed. Male Sprague-Dawley rats were pretreated with brusatol (Bru, 0.4 mg/kg/2 days, i.p.), an inhibitor of Nrf2, and BA (10, 25, 50 mg/kg/day, i.g.) for 3 days and injected with LPS (10 mg/kg, i.p.) at the 4th day. Rats were anesthetized and killed by cervical dislocation after they were treated with LPS for 4 h. Thoracic aortas were immediately dissected out to determine contraction and relaxation using the organ bath system. Pro-inflammatory factors interleukin-1β (IL-1β) and tumor necrosis factor-α (TNF-α) and oxidative stress were measured in aortic tissues and plasma. mRNA expression of Nrf2-regulated antioxidative enzymes, including superoxide dismutase (SOD), glutathione peroxidase (GPx), and heme oxygenase-1 (HO-1), in rat aortas was determined. Increases of IL-1β, TNF-α, nitric oxide, and malondialdehyde and the decrease of glutathione induced by LPS were significantly attenuated by pretreatment with different doses of BA in plasma and aortas (p < 0.05 versus LPS), all of which were blocked by Bru (p < 0.01). Inhibition of phenylephrine (PE)- and KCl-induced contractions and acetylcholine (ACh)-induced vasodilatation in aortas from LPS-challenged rats was dose-dependently reduced by BA (p < 0.05; percentage improvements by BA in PE-induced contraction were 55.38%, 96.41%, and 104.33%; those in KCl-induced contraction were 15.11%, 23.96%, and 22.96%; and those in ACh-induced vasodilatation were 16.08%, 42.99%, and 47.97%), all of which were reversed by Bru (p < 0.01). Improvements of SOD, GPx, and HO-1 mRNA expression conferred by BA in LPS-challenged rat aortas were inhibited by Bru (p < 0.01; 145.45% versus 17.42%, 160.69% versus 22.76%, and 166.88% versus 23.57%). These findings suggest that BA attenuates impairments of aortic contraction and relaxation in LPS-challenged rats by activating Nrf2-regulated antioxidative pathways.
Identifiants
pubmed: 31352642
doi: 10.1007/s10787-019-00622-4
pii: 10.1007/s10787-019-00622-4
doi:
Substances chimiques
Antioxidants
0
Interleukin-1beta
0
Lipopolysaccharides
0
NF-E2-Related Factor 2
0
NF-kappa B
0
Pentacyclic Triterpenes
0
Triterpenes
0
Tumor Necrosis Factor-alpha
0
Nitric Oxide
31C4KY9ESH
Malondialdehyde
4Y8F71G49Q
Superoxide Dismutase
EC 1.15.1.1
Glutathione
GAN16C9B8O
Betulinic Acid
4G6A18707N
Types de publication
Journal Article
Langues
eng
Sous-ensembles de citation
IM
Pagination
165-174Subventions
Organisme : National Natural Science Foundation of China
ID : 81772035
Organisme : Xinmiao Talents Program of Zhejiang Province
ID : 2018R427001
Organisme : Natural Science Program of Hangzhou Medical College
ID : 2016XZA04
Organisme : Program of Cultivating Zhejiang Provincial High-level Personnel in Health
ID : Excellent Medical Younger in 2018
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