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

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机构: [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-Macau 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, Macau University of Science and Technology, Macau, 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
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关键词: aconitine cardiotoxicity individual differences hemoglobin subunit beta nitrogen monoxide ABHD5/AMPK/HDAC4 axis

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.© 2024. The Author(s).

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出版当年[2023]版:
大类 | 1 区 医学
小类 | 1 区 药学 2 区 化学:综合
最新[2025]版:
大类 | 2 区 医学
小类 | 1 区 药学 2 区 化学:综合
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第一作者机构: [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-Macau Joint Lab on Chinese Medicine and Immune Disease Research, International Institute for Translational Chinese Medicine, Guangzhou University of Chinese Medicine, Guangzhou 510006, China
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通讯机构: [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-Macau 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, Macau University of Science and Technology, Macau, China
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