Li Miao, Liu Xin, He Yongpeng, Zheng Qingyin, Wang Min, Wu Yu, Zhang Yuanpeng, Wang Chaoyun
School of Pharmaceutical Sciences, Binzhou Medical University, No. 346, Guanhai Road, Laishan District, Yantai 264003, PR China.
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.
Eur J Pharmacol. 2017 Feb 15;797:124-133. doi: 10.1016/j.ejphar.2017.01.027. Epub 2017 Jan 21.
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 (AT receptor), 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/AT receptor 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.
血管紧张素II（Ang II）作为内皮功能障碍的关键因素，参与内皮氧化损伤和炎症反应，这在所有心血管疾病（CVD）中均有体现。从雷公藤中提取的雷公藤红素是一种具有抗氧化和抗炎活性的天然化合物。在本研究中，观察了雷公藤红素对Ang II诱导的人脐静脉内皮细胞（HUVEC）损伤的保护作用，并阐明了其机制。与对照组相比，Ang II显著增加烟酰胺腺嘌呤二核苷酸磷酸（NADPH）氧化酶活性，提高活性氧水平和促炎细胞因子，降低抗氧化酶活性，抑制细胞活力并促进细胞凋亡。它通过抑制核因子红细胞2相关因子2（Nrf2），增加Nox2和血管紧张素II 1型受体（AT受体）的表达水平，并诱导细胞外信号调节激酶（ERK1/2）磷酸化来实现这一点。相比之下，雷公藤红素通过激活Nrf2、抑制Nox2/AT受体表达和上调ERK1/2磷酸化，有效抑制活性氧生成，改善内皮细胞活性，并减轻Ang II介导的HUVEC损伤。用Nrf2的特异性抑制剂布沙替尼处理后，雷公藤红素对Ang II诱导的HUVEC损伤的保护作用明显减轻。综上所述，雷公藤红素诱导的Nrf2激活和NADPH氧化酶活性抑制对于抑制Ang II介导的内皮功能障碍至关重要，并证明了雷公藤红素在CVD治疗中的潜在应用。
