广州中医药大学卢琳琳、刘中秋，北京中医药大学陈建新等人的最新研究，揭示了HBB通过干扰ABHD5/AMPK/HDAC4轴参与乌头碱诱导的个体化小鼠心脏毒性。相关论文于2024年3月11日发表在《中国药理学报》杂志上。

在这项研究中，该课题组人员研究了乌头碱(aconitine, AC)诱导心脏毒性的个体差异，生物标志物和潜在的机制。多样性远交种(DO)小鼠作为一种模拟临床个体化遗传异质性模型。小鼠口服AC(0.3、0.6、0.9 mg·kg-1·d-1) 7天。该课题组人员发现，AC引发的DO小鼠心脏毒性与临床患者的特征相似。最重要的是，在DO小鼠中存在显著的个体差异(变异系数为34.08% ~ 53.17%)。在AC耐受和AC敏感小鼠中进行的RNA测序表明，血液中的毒性应答蛋白血红蛋白亚单位β（HBB）在AC敏感小鼠中特异性富集，与人类有89%的同源性。

此外，该研究团队发现HBB过表达可显著加剧AC诱导的心脏毒性，而HBB敲低可显著减轻心肌细胞的细胞死亡。课题组研究人员发现AC可以触发溶血，并特异性地与无细胞血红蛋白(cf-Hb)中的HBB结合，从而过度促进NO清除并降低心脏保护S-亚硝基化。同时，AC与HBB结合可增强HBB与ABHD5和AMPK的结合，从而减少HDAC-NT的生成，导致心肌细胞死亡。本研究不仅证明了HBB实现了血液中AC的新靶点，而且首次为HBB作为确定附子诱发心脏毒性个体差异的新型生物标志物提供了线索。

研究人员表示，乌头的根（学名：Aconitum carmichaelii Debx.，又名附子）是中国常用的一种中药，在拯救重病患者方面具有显著功效。附子中的一种关键有毒化合物乌头碱(aconitine, AC)可能引发不可预测的心脏毒性，具有高度个体性，这阻碍了附子的安全应用。

附：英文原文

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

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

Issue&Volume: 2024-03-11

Abstract: 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, 0.9mg·kg1·d1) 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.

DOI: 10.1038/s41401-023-01206-3

Source: https://www.nature.com/articles/s41401-023-01206-3