HBB contributes to individualized aconitine-induced cardiotoxicity in mice via interfering with ABHD5/AMPK/HDAC4 axis  

作　　者：Ya-juan Guo Jing-jing Yao Zhen-zhen Guo Ming Ding Kun-lin Zhang Qing-hong Shen Yu Li Shao-fang Yu Ting Wan Fu-ping Xu Ying Wang Xiao-xiao Qi Jin-jun Wu Jian-xin Chen Zhong-qiu Liu Lin-lin Lu 

机构地区：[1]Joint Laboratory for Translational Cancer Research of Chinese Medicine of the Ministry of Education of the People’s Republic of China,Guangdong-Hong Kong-Macao Joint Lab on Chinese Medicine and Immune Disease Research,International Institute for Translational Chinese Medicine,Guangzhou University of Chinese Medicine,Guangzhou,510006,China [2]State Key Laboratory of Quality Research in Chinese Medicine,Macao University of Science and Technology,Macao,China [3]Guandong Provincial hospital of Chinese Medicine,Guangzhou University of Chinese Medicine,Guangzhou,Guangdong,510006,China [4]Beijing University of Chinese Medicine,Beijing,100029,China

出　　处：《Acta Pharmacologica Sinica》2024年第6期1224-1236,共13页中国药理学报（英文版）

基　　金：supported by National Natural Science Foundation of China(82022074 and 82274196);the 2020 Guangdong Provincial Science and Technology Innovation Strategy Special Fund(Guangdong-Hong Kong-Macao Joint Lab,2020B1212030006);Key-Area Research and Development Program of Guangdong Province(2020B1111100004).

摘　　要：The root of Aconitum carmichaelii Debx.(Fuzi)is an herbal medicine used in China that exerts significant efficacy in rescuing patients from severe diseases.A key toxic compound in Fuzi,aconitine(AC),could trigger unpredictable cardiotoxicities with high-individualization,thus hinders safe application of Fuzi.In this study we investigated the individual differences of AC-induced cardiotoxicities,the biomarkers and underlying mechanisms.Diversity Outbred(DO)mice were used as a genetically heterogeneous model for mimicking individualization clinically.The mice were orally administered AC(0.3,0.6,0.9 mg·kg^(-1)·d^(-1))for 7 d.We found that AC-triggered cardiotoxicities in DO mice shared similar characteristics to those observed in clinic patients.Most importantly,significant individual differences were found in DO mice(variation coefficients:34.08%-53.17%).RNA-sequencing in AC-tolerant and AC-sensitive mice revealed that hemoglobin subunit beta(HBB),a toxic-responsive protein in blood with 89% homology to human,was specifically enriched in AC-sensitive mice.Moreover,we found that HBB overexpression could significantly exacerbate AC-induced cardiotoxicity while HBB knockdown markedly attenuated cell death of cardiomyocytes.We revealed that AC could trigger hemolysis,and specifically bind to HBB in cell-free hemoglobin(cf-Hb),which could excessively promote NO scavenge and decrease cardioprotective S-nitrosylation.Meanwhile,AC bound to HBB enhanced the binding of HBB to ABHD5 and AMPK,which correspondingly decreased HDAC-NT generation and led to cardiomyocytes death.This study not only demonstrates HBB achievement a novel target of AC in blood,but provides the first clue for HBB as a novel biomarker in determining the individual differences of Fuzi-triggered cardiotoxicity.

关 键 词：ACONITINE CARDIOTOXICITY individual differences hemoglobin subunit beta nitrogen monoxide ABHD5/AMPK/HDAC4 axis 

分 类 号：R285[医药卫生—中药学]