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Methuosis: an excessive cytoplasm vacuolization related cell death mediatesmaduramicin-induced cardiotoxicity

Gao Xiu-geJi Chun-leiZheng Yu-lingGuo Da-weiPeng LinJi HuiJiang Shan-xiang

College of Veterinary Medicine,Nanjing Agricultural University

摘要:Maduramicin frequently triggers severe cardiotoxicity in domestic animals as well as human accidentally. Apoptotic and non-apoptotic cell death contribute to the serious myocardial damage in clinic. The mechanisms underlying maduramicin-induced non-apoptotic cell death remain largely unknown. In present study, we aimed to elucidate the morphological characteristics and regulatory mechanisms of cytoplasmic vacuolization related cell death induced by maduramicin. H9 c2 cells and primary chicken myocardial cells, as well as broiler chickens and rats were used as experimental models.We found that maduramicintriggered numerous phase-lucent vacuoles, which occupied large area of cytoplasm in primary and passage myocardial cells. The cytoplasmic vacuoles induced by maduramicin were generated in a concentration and time dependent manner, along with increased cell death rate.Furthermore, maduramicin-induced cytoplasmic vacuoles are generated from micropinocytosis, rather than the swelling of mitochondria, lysosome, endoplasmic reticulum and Golgi apparatus, demonstrat-ing by the internalization of Dextran-AF 488 into myocardial cells. Intriguingly, the vacuoles acquired some characteristics of late endosomes and lysosomes rather than early endosomes and autophago-somes.Vacuolar H+-ATPase inhibitor bafilomycin A1 efficiently prevented the generation of cytoplasmic vacuoles and decreased the cardiotoxicityinduced by maduramicin. Mechanism studying indicated that maduramicin activated H-Ras-Rac1 signaling pathway. However, the pharmacological inhibition and siRNA knockdown of Rac1 rescued maduramicin-induced cytotoxicity of H9 c2 cells but did not alleviate cytoplasmic vacuolization. Moreover, maduramicin-induced methuosis was confirmed in rats and chickens with extensive vacuolar degenerationof myocardium. Proteomic analysis further indicated differentially expressed proteinswere significant enriched in SNARE interactions in vesicular transport, ECM-receptor interaction, PPAR signaling pathway, cell adhesion, regulation of actin cytoskeleton and JakSTAT signaling pathway. In summary, methuosis, a novel non-apoptotic cell death, mediatesmaduramicin-induced cardiotoxicity in noncanonical programmed pathways.
会议名称:

第九届亚洲毒理学大会暨中国毒理学会第八次中青年科技论坛

会议时间:

2021-10-20

会议地点:

中国浙江杭州

  • 专辑:

    农业科技

  • 专题:

    畜牧与动物医学

  • DOI:

    10.26914/c.cnkihy.2021.052680

  • 分类号:

    S859.8

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