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.