title: Celastrol attenuates angiotensin II mediated human umbilical vein endothelial cells damage through activation of Nrf2/ERK1/2/Nox2 signal pathway.
abstract: Angiotensin II (Ang II), as a crucial factor of endothelial dysfunction, participates in endothelial oxidative damage and inflammation, which is present in all cardiovascular disease (CVD). Celastrol, extracted from Trypterygiun wilfordii Hook F. ("Thunder of God Vine"), is a natural compound with antioxidant and anti-inflammatory activities. In this study, the protective effects of celastrol on human umbilical vein endothelial cell (HUVEC) injury induced by Ang II were observed and its mechanisms were elucidated. Compared with the control group, Ang II significantly increased nicotinamide adenine dinucleotide phosphate (NADPH) oxidase activity, enhanced reactive oxygen species levels and proinflammatory cytokines, decreased antioxidant enzyme activities, and suppressed cellular viability and promoted cell apoptosis. It accomplished this via inhibition of the nuclear factor erythroid 2-related factor 2 (Nrf2), increasing the expression levels of Nox2 and AngII type 1 receptor (AT1receptor), and inducing the phosphorylation of extracellular signal regulated kinase (ERK1/2). In contrast, celastrol effectively suppressed reactive oxygen species generation, improved endothelial cell activity, and ameliorated Ang II-mediated HUVEC injury through activation of Nrf2, inhibition of Nox2/AT1receptor expression, and upregulated phosphorylation of ERK1/2. After treatment with brusatol, a specific inhibitor of Nrf2, the protective effects of celastrol on Ang II-induced damage in HUVECs were remarkably alleviated. Taken together, celastrol-induced activation of Nrf2 and inhibition of NADPH oxidase activity were critical for the inhibition of Ang II-mediated endothelial dysfunction, and demonstrated the potential application of celastrol in CVD therapy.
authors.affiliation: School of Pharmaceutical Sciences, Binzhou Medical University, No. 346, Guanhai Road, Laishan District, Yantai 264003, PR China.
authors.forename: Miao
authors.initials: M
authors.lastname: Li
authors.affiliation: School of Pharmaceutical Sciences, Binzhou Medical University, No. 346, Guanhai Road, Laishan District, Yantai 264003, PR China.
authors.forename: Xin
authors.initials: X
authors.lastname: Liu
authors.affiliation: School of Pharmaceutical Sciences, Binzhou Medical University, No. 346, Guanhai Road, Laishan District, Yantai 264003, PR China.
authors.forename: Yongpeng
authors.initials: Y
authors.lastname: He
authors.affiliation: School of Pharmaceutical Sciences, Binzhou Medical University, No. 346, Guanhai Road, Laishan District, Yantai 264003, PR China; Department of Otolaryngology-Head & Neck Surgery, Case Western Reserve University, Cleveland 44106, USA.
authors.forename: Qingyin
authors.initials: Q
authors.lastname: Zheng
authors.affiliation: School of Pharmaceutical Sciences, Binzhou Medical University, No. 346, Guanhai Road, Laishan District, Yantai 264003, PR China.
authors.forename: Min
authors.initials: M
authors.lastname: Wang
authors.affiliation: Clinical college, Binzhou Medical University,Yantai 264003, PR China.
authors.forename: Yu
authors.initials: Y
authors.lastname: Wu
authors.affiliation: Clinical college, Binzhou Medical University,Yantai 264003, PR China.
authors.forename: Yuanpeng
authors.initials: Y
authors.lastname: Zhang
authors.affiliation: School of Pharmaceutical Sciences, Binzhou Medical University, No. 346, Guanhai Road, Laishan District, Yantai 264003, PR China. Electronic address: ytwcy@126.com.
authors.forename: Chaoyun
authors.initials: C
authors.lastname: Wang
mesh_terms: D000804:Angiotensin II / Q000378:metabolism*; D000893:Anti-Inflammatory Agents / Q000494:pharmacology; D000975:Antioxidants / Q000494:pharmacology; D017209:Apoptosis / Q000187:drug effects; D002470:Cell Survival / Q000187:drug effects; D005786:Gene Expression Regulation / Q000187:drug effects; D061307:Human Umbilical Vein Endothelial Cells / Q000166:cytology* / Q000187:drug effects* / Q000378:metabolism; D006801:Humans; D020935:MAP Kinase Signaling System / Q000187:drug effects*; D008562:Membrane Glycoproteins / Q000378:metabolism*; D000074662:NADPH Oxidase 2; D019255:NADPH Oxidases / Q000378:metabolism*; D051267:NF-E2-Related Factor 2 / Q000378:metabolism*; D053978:Pentacyclic Triterpenes; D017382:Reactive Oxygen Species / Q000378:metabolism; D044140:Receptor, Angiotensin, Type 1 / Q000378:metabolism; D014315:Triterpenes / Q000494:pharmacology*
chemical_list: D000893:Anti-Inflammatory Agents; D000975:Antioxidants; D008562:Membrane Glycoproteins; D051267:NF-E2-Related Factor 2; C495635:NFE2L2 protein, human; D053978:Pentacyclic Triterpenes; D017382:Reactive Oxygen Species; D044140:Receptor, Angiotensin, Type 1; D014315:Triterpenes; D000804:Angiotensin II; C056558:CYBB protein, human; D000074662:NADPH Oxidase 2; D019255:NADPH Oxidases; C050414:celastrol
keywords: Angiotensin II; Celastrol; Nicotinamide adenine dinucleotide phosphate (NADPH) oxidase; Nox2; Nuclear factor erythroid 2–related factor 2; Reactive oxygen species