title: Histone deacetylase-high mobility group box-1 pathway targeted by hypaconitine suppresses the apoptosis of endothelial cells.
abstract: 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.
authors.affiliation: 1 Department of Anatomy, Guangzhou University of Chinese Medicine, Guangzhou 510405, China.
authors.forename: Ye
authors.initials: Y
authors.lastname: Bai
authors.affiliation: 2 Department of Internal Medicine, Affiliated Shenzhen Hospital, Guangzhou University of Chinese Medicine, Shenzhen 518033, China.
authors.forename: Shaohui
authors.initials: S
authors.lastname: Du
authors.affiliation: 1 Department of Anatomy, Guangzhou University of Chinese Medicine, Guangzhou 510405, China.
authors.forename: Fei
authors.initials: F
authors.lastname: Li
authors.affiliation: 1 Department of Anatomy, Guangzhou University of Chinese Medicine, Guangzhou 510405, China.
authors.forename: Fengyuan
authors.initials: F
authors.lastname: Huang
authors.affiliation: 1 Department of Anatomy, Guangzhou University of Chinese Medicine, Guangzhou 510405, China.
authors.forename: Rudong
authors.initials: R
authors.lastname: Deng
authors.affiliation: 1 Department of Anatomy, Guangzhou University of Chinese Medicine, Guangzhou 510405, China.
authors.forename: Jianhong
authors.initials: J
authors.lastname: Zhou
authors.affiliation: 1 Department of Anatomy, Guangzhou University of Chinese Medicine, Guangzhou 510405, China.
authors.forename: Dongfeng
authors.initials: D
authors.lastname: Chen
mesh_terms: D000157:Aconitine / Q000031:analogs & derivatives* / Q000494:pharmacology; D031841:Aconitum / Q000737:chemistry; D017209:Apoptosis / Q000187:drug effects* / Q000502:physiology; D015153:Blotting, Western; D002460:Cell Line; D042783:Endothelial Cells / Q000187:drug effects* / Q000502:physiology; D004797:Enzyme-Linked Immunosorbent Assay; D024243:HMGB1 Protein / Q000187:drug effects* / Q000502:physiology; D006655:Histone Deacetylases / Q000187:drug effects* / Q000502:physiology; D006801:Humans; D020411:Oligonucleotide Array Sequence Analysis; D060888:Real-Time Polymerase Chain Reaction; D015398:Signal Transduction / Q000187:drug effects / Q000502:physiology; D000099186:Histone Deacetylase 3
chemical_list: D000157:Aconitine; D024243:HMGB1 Protein; D006655:Histone Deacetylases; D000099186:Histone Deacetylase 3; C585491:HMGB1 protein, human; C058309:hypaconitine
keywords: HDAC3; HMGB1; Hypaconitine; OXLDL; apoptosis; endothelial cells