PMID- 31352642 OWN - NLM STAT- MEDLINE DCOM- 20201117 LR - 20221207 IS - 1568-5608 (Electronic) IS - 0925-4692 (Linking) VI - 28 IP - 1 DP - 2020 Feb TI - Betulinic acid attenuates lipopolysaccharide-induced vascular hyporeactivity in the rat aorta by modulating Nrf2 antioxidative function. PG - 165-174 LID - 10.1007/s10787-019-00622-4 [doi] AB - 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-1beta (IL-1beta) and tumor necrosis factor-alpha (TNF-alpha) 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-1beta, TNF-alpha, 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. FAU - Bai, Yao-Yao AU - Bai YY AD - School of Basic Medical Sciences & Forensic Medicine, Hangzhou Medical College, Hangzhou, 310053, China. AD - School of Radiology, Hangzhou Medical College, Hangzhou, 310053, China. FAU - Yan, Dong AU - Yan D AD - School of Basic Medical Sciences & Forensic Medicine, Hangzhou Medical College, Hangzhou, 310053, China. AD - School of Radiology, Hangzhou Medical College, Hangzhou, 310053, China. FAU - Zhou, Hui-Ying AU - Zhou HY AD - School of Basic Medical Sciences & Forensic Medicine, Hangzhou Medical College, Hangzhou, 310053, China. AD - School of Radiology, Hangzhou Medical College, Hangzhou, 310053, China. FAU - Li, Wei-Xin AU - Li WX AD - School of Basic Medical Sciences & Forensic Medicine, Hangzhou Medical College, Hangzhou, 310053, China. AD - School of Laboratory Medicine, Hangzhou Medical College, Hangzhou, 310053, China. FAU - Lou, Yang-Yun AU - Lou YY AD - School of Basic Medical Sciences & Forensic Medicine, Hangzhou Medical College, Hangzhou, 310053, China. FAU - Zhou, Xin-Ru AU - Zhou XR AD - School of Basic Medical Sciences & Forensic Medicine, Hangzhou Medical College, Hangzhou, 310053, China. FAU - Qian, Ling-Bo AU - Qian LB AD - School of Basic Medical Sciences & Forensic Medicine, Hangzhou Medical College, Hangzhou, 310053, China. bioqian@163.com. FAU - Xiao, Chi AU - Xiao C AD - School of Basic Medical Sciences & Forensic Medicine, Hangzhou Medical College, Hangzhou, 310053, China. xcier@163.com. LA - eng GR - 81772035/National Natural Science Foundation of China/ GR - 2018R427001/Xinmiao Talents Program of Zhejiang Province/ GR - 2016XZA04/Natural Science Program of Hangzhou Medical College/ GR - Excellent Medical Younger in 2018/Program of Cultivating Zhejiang Provincial High-level Personnel in Health/ PT - Journal Article DEP - 20190727 PL - Switzerland TA - Inflammopharmacology JT - Inflammopharmacology JID - 9112626 RN - 0 (Antioxidants) RN - 0 (Interleukin-1beta) RN - 0 (Lipopolysaccharides) RN - 0 (NF-E2-Related Factor 2) RN - 0 (NF-kappa B) RN - 0 (Pentacyclic Triterpenes) RN - 0 (Triterpenes) RN - 0 (Tumor Necrosis Factor-alpha) RN - 31C4KY9ESH (Nitric Oxide) RN - 4Y8F71G49Q (Malondialdehyde) RN - EC 1.15.1.1 (Superoxide Dismutase) RN - GAN16C9B8O (Glutathione) RN - 4G6A18707N (Betulinic Acid) SB - IM MH - Animals MH - Antioxidants/*metabolism MH - Aorta, Thoracic/*drug effects/metabolism MH - Glutathione/metabolism MH - Interleukin-1beta/metabolism MH - Lipopolysaccharides/*pharmacology MH - Male MH - Malondialdehyde/metabolism MH - NF-E2-Related Factor 2/*metabolism MH - NF-kappa B/metabolism MH - Nitric Oxide/metabolism MH - Oxidative Stress/drug effects MH - Pentacyclic Triterpenes MH - Rats MH - Rats, Sprague-Dawley MH - Superoxide Dismutase/metabolism MH - Triterpenes/*pharmacology MH - Tumor Necrosis Factor-alpha/metabolism MH - Betulinic Acid OTO - NOTNLM OT - Betulinic acid OT - Lipopolysaccharide OT - Nrf2 OT - Oxidative stress OT - Vascular hyporeactivity EDAT- 2019/07/29 06:00 MHDA- 2020/11/18 06:00 CRDT- 2019/07/29 06:00 PHST- 2019/02/24 00:00 [received] PHST- 2019/07/17 00:00 [accepted] PHST- 2019/07/29 06:00 [pubmed] PHST- 2020/11/18 06:00 [medline] PHST- 2019/07/29 06:00 [entrez] AID - 10.1007/s10787-019-00622-4 [pii] AID - 10.1007/s10787-019-00622-4 [doi] PST - ppublish SO - Inflammopharmacology. 2020 Feb;28(1):165-174. doi: 10.1007/s10787-019-00622-4. Epub 2019 Jul 27.