Bai Ye, Du Shaohui, Li Fei, Huang Fengyuan, Deng Rudong, Zhou Jianhong, Chen Dongfeng
1 Department of Anatomy, Guangzhou University of Chinese Medicine, Guangzhou 510405, China.
2 Department of Internal Medicine, Affiliated Shenzhen Hospital, Guangzhou University of Chinese Medicine, Shenzhen 518033, China.
Exp Biol Med (Maywood). 2017 Mar;242(5):527-535. doi: 10.1177/1535370216685433. Epub 2017 Jan 5.
Hypaconitine is an active component of Aconitum carmichaelii Debx, a Chinese medicinal herb for the treatment of cardiovascular diseases, but the mechanism underlying its effect remains elusive. In this study, we found that hypaconitine, rather than aconitum alkaloids in A. carmichaelii (e.g. aconitine, mesaconitine and benzoylaconitine), prevented endothelial cells from damage due to oxidized low-density lipoprotein (oxLDL) challenge. Cleaved caspase 3 expression in endothelial cells was up-regulated by oxLDL and markedly attenuated by hypaconitine, suggesting that hypaconitine inhibited the oxLDL-induced cell apoptosis. Microarray analysis revealed that histone deacetylase 3 (HDAC3) was significantly increased by hypaconitine. The cytoplasmic relocation and extracellular release of high-mobility group box 1 (HMGB1, an HDAC3 downstream effector) in endothelial cells were significantly increased by oxLDL and markedly decreased by hypaconitine. The effect of hypaconitine on the oxLDL-induced apoptosis and HMGB1 release in endothelial cells was significantly reduced by the suppression of HDAC3 by siRNA or a specific inhibitor. Thus, this study proves that the histone deacetylase-HMGB1 pathway targeted by hypaconitine suppresses the apoptosis of endothelial cells. Our findings are of therapeutic significance and provide the potential of hypaconitine exploitation. Impact statement First, our study shows the antiapoptosis effect of Aconitum carmichaelii and its active component hypaconitine on endothelial cells. It may provide new strategies for the treatment of diseases involving endothelium damage. Second, this finding indicates the function of hypaconitine in regulating HDAC3-HMGB1 pathway, which suggests a new anti-inflammatory therapy. Third, due to its poisonousness, A. carmichaelii is always used with caution in clinics. Thus, the identification of hypaconitine as an active component of A. carmichaelii could contribute to the development of toxicity-decreasing procedure for A. carmichaelii.
次乌头碱是治疗心血管疾病的中药材乌头的一种活性成分，但其作用机制尚不清楚。在本研究中，我们发现，次乌头碱而非乌头中的乌头生物碱（如乌头碱、中乌头碱和苯甲酰乌头碱）可防止内皮细胞因氧化型低密度脂蛋白（oxLDL）攻击而受损。oxLDL可上调内皮细胞中裂解的半胱天冬酶3的表达，而次乌头碱可显著减弱这种上调，这表明次乌头碱可抑制oxLDL诱导的细胞凋亡。基因芯片分析显示，次乌头碱可显著增加组蛋白去乙酰化酶3（HDAC3）的表达。oxLDL可显著增加内皮细胞中高迁移率族蛋白B1（HMGB1，一种HDAC3下游效应分子）的胞质转位和细胞外释放，而次乌头碱可显著减少这种释放。通过小干扰RNA或特异性抑制剂抑制HDAC3后，次乌头碱对oxLDL诱导的内皮细胞凋亡和HMGB1释放的作用显著降低。因此，本研究证明，次乌头碱靶向的组蛋白去乙酰化酶-HMGB1途径可抑制内皮细胞凋亡。我们的研究结果具有治疗意义，并为次乌头碱的开发提供了潜力。影响声明：首先，我们的研究显示了乌头及其活性成分次乌头碱对内皮细胞的抗凋亡作用。这可能为涉及内皮损伤的疾病治疗提供新策略。其次，这一发现表明了次乌头碱在调节HDAC3-HMGB1途径中的作用，这提示了一种新的抗炎治疗方法。第三，由于乌头有毒，临床上使用时一直很谨慎。因此，将次乌头碱鉴定为乌头的活性成分有助于开发降低乌头毒性的方法。
