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作者：黄燕宁广西医科大学

学位级别：硕士

目的探讨线粒体自噬受体蛋白bnip3是否通过调节ROS生成介导MnCl2诱导具有多巴胺能作用的SH-SY5Y人神经母细胞瘤细胞发生线粒体自噬。方法⑴.细胞毒性检测:取对数生长期的人神经母细胞瘤SH-SY5Y细胞,使用细胞增殖/毒性检测试剂盒CCK-8检... 详细信息

目的探讨线粒体自噬受体蛋白bnip3是否通过调节ROS生成介导MnCl2诱导具有多巴胺能作用的SH-SY5Y人神经母细胞瘤细胞发生线粒体自噬。方法⑴.细胞毒性检测:取对数生长期的人神经母细胞瘤SH-SY5Y细胞,使用细胞增殖/毒性检测试剂盒CCK-8检测不同时间及不同浓度MnCl2作用下SH-SY5Y细胞的细胞活力;使用流式细胞仪检测MnCl2作用下SH-SY5Y细胞线粒体膜电位改变情况。⑵.MnCl2诱导SH-SY5Y细胞线粒体自噬检测:经MnCl2处理24h后采用蛋白免疫印记法检测线粒体自噬受体蛋白bnip3、线粒体外膜标记蛋白TOMM20的表达量及自噬标记蛋白LC3-I向LC3-II的转化情况;应用透射电子显微镜直接观察MnCl2作用下SH-SY5Y细胞的线粒体形态改变情况及线粒体自噬是否发生;应用自噬抑制剂3-MA反证MnCl2作用下SH-SY5Y细胞内线粒体自噬体是否形成;使用荧光共聚焦显微镜检测MnCl2作用下线粒体是否通过溶酶体途径降解。⑶.ROS的生成量及ROS参与MnCl2诱导SH-SY5Y细胞线粒体自噬检测:使用酶标仪检测MnCl2作用下SH-SY5Y细胞内ROS的生成量,并使用抗氧化剂NAC反证MnCl2是否可导致ROS生成增多;应用蛋白免疫印记法检测经抗氧化剂NAC预处理后线粒体自噬受体蛋白bnip3、线粒体外膜标记蛋白TOMM20的表达量及自噬标记蛋白LC3-I向LC3-II的转化情况;应用透射电镜及加用自噬抑制剂3-MA进一步检测ROS是否参与MnCl2诱导SH-SY5Y细胞发生线粒体自噬。⑷.bnip3通过调节ROS生成介导MnCl2诱导SH-SY5Y细胞发生线粒体自噬及神经毒性检测:运用免疫共沉淀法验证SH-SY5Y细胞中线粒体自噬受体蛋白bnip3与自噬标记蛋白LC3蛋白是否能相互结合;使用bnip3 shRNA干扰SH-SY5Y细胞中bnip3的表达,观察bnip3低表达对MnCl2诱导SH-SY5Y细胞线粒体形态改变及线粒体自噬、ROS生成、自噬标记蛋白LC3I向LC3Ⅱ转换及线粒体外膜标记蛋白TOMM20表达量的影响。结果⑴.MnCl2可使SH-SY5Y细胞活力呈时间及浓度依赖性下降,并使线粒体膜电位呈浓度依赖性降低。⑵.MnCl2可使粒体自噬受体蛋白bnip3的表达量及自噬标记蛋白LC3-I向LC3-II的转化呈浓度依赖性升高并使线粒体外膜标记蛋白TOMM20的表达呈浓度依赖性降低;400μmol/L MnCl2作用24小时后可使SH-SY5Y细胞内线粒体膨胀、溶解或凝聚、变性并使线粒体自噬小体形成增多,且MnCl2作用下可使线粒体标记物MitoTracker?及溶酶体标记物LysoTracker?荧光共定位情况增多;自噬抑制剂3-MA与400μmol/L MnCl2共培养可减少SH-SY5Y细胞内线粒体自噬小体的形成并减少线粒体标记物MitoTracker?与溶酶体标记物LysoTracker?荧光共定位情况,其还可降低线粒体自噬受体蛋白bnip3的表达量及减少自噬标记蛋白LC3-I向LC3-II的转化并使线粒体外膜标记蛋白TOMM20的表达升高。⑶.SH-SY5Y细胞内ROS生成随MnCl2浓度的加大而增多,使用抗氧化剂NAC可减轻400μmol/L MnCl2作用下ROS的产生,同时NAC还可降低线粒体自噬受体蛋白bnip3的表达量及减少自噬标记蛋白LC3-I向LC3-II的转化并使线粒体外膜标记蛋白TOMM20的表达增多及减少线粒体自噬小体形成,而自噬抑制剂3-MA并不能抑制ROS生成。⑷.SH-SY5Y细胞中的线粒体自噬受体蛋白bnip3和自噬标记蛋白LC3可有效地相互结合;干扰bnip3表达可减少自噬标记蛋白LC3-I向LC3-II转化并使线粒体外膜标记蛋白TOMM20的表达增多,同时bnip3表达减少还可使400μmol/L MnCl2作用24小时后的SH-SY5Y细胞内的线粒体自噬体形成减少,且在400μmol/L MnCl2作用下,bnip3低表达细胞株的ROS生成及线粒体膜电位丢失减少。结论线粒体自噬受体蛋白bnip3通过调节ROS的生成介导MnCl2诱导多巴胺能神经元线粒体自噬。bnip3的这种功能可能是锰致神经毒性的作用机制之一。

关键词： MnCl2 SH-SY5Y细胞线粒体自噬 ROS bnip3

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组蛋白去乙酰化下调对肾细胞癌bnip3基因表达的影响

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四川大学学报（医学版） 2017年第3期48卷 384-388,393页

作者：刘健帮王海舟刘振华徐苗李响四川大学华西医院泌尿外科成都610041 四川大学华西医院泌尿外科研究所成都610041 四川大学华西医院病理研究室成都610041

目的探讨肾细胞癌中线粒体促凋亡蛋白bnip3表达下调机制。方法运用CCK-8法及流式细胞技术检测组蛋白去乙酰化酶抑制剂曲古霉素A(TSA)对肾癌细胞株786-O、ACHN、A498增殖、凋亡的影响;运用实时荧光定量PCR(Q-PCR)和蛋白质免疫印记(Wester... 详细信息

目的探讨肾细胞癌中线粒体促凋亡蛋白bnip3表达下调机制。方法运用CCK-8法及流式细胞技术检测组蛋白去乙酰化酶抑制剂曲古霉素A(TSA)对肾癌细胞株786-O、ACHN、A498增殖、凋亡的影响;运用实时荧光定量PCR(Q-PCR)和蛋白质免疫印记(Western blot)技术检测TSA对肾癌细胞bnip3表达的影响;运用染色质免疫沉淀(ChIP)技术检测TSA对肾癌细胞bnip3基因启动子区组蛋白H3乙酰化状态的影响。结果经TSA处理后,3种肾癌细胞增殖均受到显著抑制(P<0.05),细胞早期凋亡明显增加,bnip3mRNA(P<0.05)和蛋白表达水平上调。786-O、ACHN的bnip3基因启动子区组蛋白H3呈去乙酰化状态,TSA恢复了其乙酰化状态;A498的bnip3基因启动子区组蛋白H3呈乙酰化状态。结论 bnip3基因启动子区组蛋白去乙酰化是其在肾癌中表达下调的主要机制,并可能参与了肾癌的发生发展。

关键词：肾细胞癌 bnip3 组蛋白去乙酰化曲古霉素 A 染色质免疫沉淀

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miR-210靶向沉默bnip3对人前列腺癌PC-3细胞凋亡的影响

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广东医学 2018年第8期39卷 1177-1181页

作者：阳宁吴磊刘俊王玲南华大学附属第二医院泌尿外科湖南衡阳421001 湖南环境生物职业技术学院湖南衡阳421001

目的观察microRNA-210(miR-210)在前列腺癌组织中的表达,并探讨其对人前列腺癌PC-3细胞凋亡的影响及分子机制。方法荧光实时定量PCR(qRT-PCR)检测30例前列腺癌组织和癌旁组织miR-210表达,并分析miR-210表达与前列腺癌患者临床病理参数... 详细信息

目的观察microRNA-210(miR-210)在前列腺癌组织中的表达,并探讨其对人前列腺癌PC-3细胞凋亡的影响及分子机制。方法荧光实时定量PCR(qRT-PCR)检测30例前列腺癌组织和癌旁组织miR-210表达,并分析miR-210表达与前列腺癌患者临床病理参数的关系。培养PC-3细胞,转染miR-210模拟物/抑制物或Bcl-2腺病毒E1B 19 k Da相关蛋白3(bnip3)siRNA,qRT-PCR检测miR-210、bnip3 mRNA表达,流式细胞术测定细胞凋亡率,Western blot检测bnip3蛋白表达。生物信息学和荧光素酶报告基因分析miR-210与bnip3靶向结合情况。结果前列腺癌组织miR-210水平明显高于癌旁组织(P<0.01),并且其表达与Gleason评分、肿瘤分期和淋巴结转移相关(P<0.05),而与年龄、吸烟史无相关性(P>0.05)。bnip3是miR-210的靶基因。miR-210模拟物转染抑制PC-3细胞凋亡、减少bnip3 mRNA和蛋白表达(P<0.01);miR-210抑制物的作用则相反(P<0.01)。bnip3 siRNA预处理废除miR-210抑制物对PC-3细胞凋亡的促进作用(P<0.01)。结论 miR-210在前列腺癌组织中表达升高,miR-210通过下调bnip3表达抑制PC-3细胞凋亡。

关键词：前列腺癌 miR-210 bnip3 凋亡

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Mitophagy is required to protect against excessive skeletal muscle atrophy following hindlimb immobilization

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JOURNAL OF BIOMEDICAL SCIENCE 2025年第1期32卷 1-20页

作者： Rahman, Fasih A. Graham, Mackenzie Q. Adam, Amanda M. Juracic, Emma S. Tupling, A. Russell Quadrilatero, Joe Univ Waterloo Fac Hlth Dept Kinesiol & Hlth Sci 200 Univ Ave West Waterloo ON N2L 3G1 Canada

BackgroundSkeletal muscle atrophy involves significant remodeling of fibers and is characterized by deficits in mitochondrial content and function. These changes are intimately connected to shifts in mitochondrial turnover, encompassing processes such as mitophagy and mitochondrial biogenesis. However, the role of these mitochondrial turnover processes in muscle atrophy remains poorly *** used a novel mitophagy reporter model, mt-Keima mice, to perform hindlimb immobilization and accurately measure mitophagy. A comprehensive set of analyses were conducted to investigate biochemical and molecular changes at the muscle and mitochondrial levels. We also performed image analyses to determine mitophagic flux. To further explore the role of mitophagy in immobilization-induced atrophy, we treated animals with N-acetylcysteine (NAC;150 mg/kg/day) to modify reactive oxygen species (ROS) signaling and colchicine (0.4 mg/kg/day) to inhibit *** study revealed that hindlimb immobilization leads to muscle weakness and atrophy of fast-twitch muscle fibers (types IIA, IIX, and IIB), with recovery observed in IIA fibers following remobilization. This atrophy was accompanied by a significant increase in mitophagic flux. Additionally, immobilization induced notable mitochondrial dysfunction, as shown by diminished respiration, increased mitochondrial ROS, and greater whole muscle lipid peroxidation. Treatment of immobilized mice with NAC enhanced mitochondrial respiration and reduced ROS generation but suppressed mitophagic flux and intensified atrophy of type IIX and IIB fibers. Additionally, administration of colchicine to immobilized mice suppressed mitophagic flux, which also exacerbated atrophy of IIX and IIB fibers. Colchicine treatment led to significant reductions in mitochondrial function, accompanied by CASP9 and CASP3 *** findings emphasize the role of mitophagy in limiting excessive muscle atrophy during immobilizati

关键词： Apoptosis bnip3 Disuse atrophy Mitophagy Mitochondria Skeletal muscle

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The Janus face of mitophagy in myocardial ischemia/reperfusion injury and recovery

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BIOMEDICINE & PHARMACOTHERAPY 2024年 173卷 116337-116337页

作者： Deng, Jiaxin Liu, Qian Ye, Linxi Wang, Shuo Song, Zhenyan Zhu, Mingyan Qiang, Fangfang Zhou, Yulin Guo, Zhen Zhang, Wei Chen, Ting Hunan Univ Chinese Med Key Lab Hunan Prov Integrated Tradit Chinese & Wes Changsha 410208 Peoples R China Tianjin Univ Tradit Chinese Med State Key Lab Modern Chinese Med Key Lab Pharmacol Tradit Chinese Med Formulae Mini Minist Educ Tianjin 301617 Peoples R China Changsha Med Univ Hunan Prov Key Lab Fundamental & Clin Res Funct Nu Changsha 410219 Peoples R China Changsha Med Univ Hunan Prov Key Lab Res & Dev Novel Pharmaceut Prep Changsha 410219 Peoples R China Changsha Med Univ Hunan Prov Key Lab TCM Agr Biogenom Changsha 410219 Peoples R China Natl Key Lab Cultivat Base Chinese Med Powder & In Changsha 410208 Peoples R China

In myocardial ischemia/reperfusion injury (MIRI), moderate mitophagy is a protective or adaptive mechanism because of clearing defective mitochondria accumulates during MIRI. However, excessive mitophagy lead to an increase in defective mitochondria and ultimately exacerbate MIRI by causing overproduction or uncontrolled production of mitochondria. Phosphatase and tensin homolog (PTEN)-induced kinase 1 (Pink1), Parkin, FUN14 domain containing 1 (FUNDC1) and B-cell leukemia/lymphoma 2 (BCL-2)/adenovirus E1B19KD interaction protein 3 (bnip3) are the main mechanistic regulators of mitophagy in MIRI. Pink1 and Parkin are mitochondrial surface proteins involved in the ubiquitin-dependent pathway, while bnip3 and FUNDC1 are mitochondrial receptor proteins involved in the non-ubiquitin-dependent pathway, which play a crucial role in maintaining mitochondrial homeostasis and mitochondrial quality. These proteins can induce moderate mitophagy or inhibit excessive mitophagy to protect against MIRI but may also trigger excessive mitophagy or insufficient mitophagy, thereby worsening the condition. Understanding the actions of these mitophagy mechanistic proteins may provide valuable insights into the pathological mechanisms underlying MIRI development. Based on the above background, this article reviews the mechanism of mitophagy involved in MIRI through Pink1/Parkin pathway and the receptor mediated pathway led by FUNDC1 and bnip3, as well as the related drug treatment, aim to provide effective strategies for the prevention and treatment of MIRI.

关键词： Myocardial ischemia/reperfusion injury The Janus face of mitophagy Pink1/Parkin FUNDC1 bnip3

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Did mitophagy follow the origin of mitochondria?

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AUTOPHAGY 2024年第5期20卷 985-993页

作者： Degli Esposti, Mauro UNAM Ctr Genom Sci Campus MorelosAv Univ S-N Col Chamilpa Cuernavaca 62210 Morelos Mexico

Mitophagy is the process of selective autophagy that removes superfluous and dysfunctional mitochondria. Mitophagy was first characterized in mammalian cells and is now recognized to follow several pathways including basal forms in specific organs. Mitophagy pathways are regulated by multiple, often interconnected factors. The present review aims to streamline this complexity and evaluate common elements that may define the evolutionary origin of mitophagy. Key issues surrounding mitophagy signaling at the mitochondrial surface may fundamentally derive from mitochondrial membrane dynamics. Elements of such membrane dynamics likely originated during the endosymbiosis of the alphaproteobacterial ancestor of our mitochondria but underwent an evolutionary leap forward in basal metazoa that determined the currently known variations in mitophagy ***: AGPAT, 1-acylglycerol-3-phosphate O-acyltransferase;ATG, autophagy related;BCL2L13, BCL2 like 13;bnip3, BCL2 interacting protein 3;bnip3L, BCL2 interacting protein 3 like;CALCOCO, calcium binding and coiled-coil domain;CL, cardiolipin;ER, endoplasmic reticulum;ERMES, ER-mitochondria encounter structure;FBXL4, F-box and leucine rich repeat protein 4;FUNDC1, FUN14 domain containing 1;GABARAPL1, GABA type A receptor associated protein like 1;HIF, hypoxia inducible factor;IMM, inner mitochondrial membrane;LBPA/BMP, lysobisphosphatidic acid;LIR, LC3-interacting region;LPA, lysophosphatidic acid;MAM, mitochondria-associated membranes;MAP1LC3/LC3, microtubule associated protein 1 light chain 3;MCL, monolysocardiolipin;ML, maximum likelihood;NBR1, NBR1 autophagy cargo receptor;OMM, outer mitochondrial membrane;PA, phosphatidic acid;PACS2, phosphofurin acidic cluster sorting protein 2;PC/PLC, phosphatidylcholine;PE, phosphatidylethanolamine;PHB2, prohibitin 2;PINK1, PTEN induced kinase 1;PtdIns, phosphatidylinositol;SAR, Stramenopiles, Apicomplexa and Rhizaria;TAX1BP1, Tax1 binding protein 1;ULK1, unc-51 like autop

关键词： bnip3 cardiolipin evolution membrane dynamics mitochondria mitophagy

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Development of a prognostic model for osteosarcoma based on macrophage polarization-related genes using machine learning: implications for personalized therapy

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CLINICAL AND EXPERIMENTAL MEDICINE 2025年第1期25卷 1-19页

作者： Zeng, Jin Wang, Dong Tong, ZhaoChen Li, ZiXin Wang, GuoWei Du, YuMeng Li, Jinsong Miao, Jinglei Chen, Shijie Cent South Univ Dept Spine Surg Xiangya Hosp 3 138 Tongzipo Rd Changsha 410013 Hunan Peoples R China East China Normal Univ Shanghai Key Lab Regulatory Biol Inst Biomed Sci Shanghai 200241 Peoples R China East China Normal Univ Sch Life Sci Shanghai 200241 Peoples R China

While neoadjuvant chemotherapy combined with surgical resection has improved the prognosis for patients with osteosarcoma, its impact on metastatic and recurrent cases remains limited. Immunotherapy is emerging as a promising alternative. However, the relationship between the phenotype of tumor-associated macrophages and the prognosis of osteosarcoma remains unclear. Differentially expressed gene during macrophage polarization were identified using the Monocle package. Weighted gene co-expression network analysis was conducted to select genes regulating macrophage polarization. The least absolute shrinkage and selection operator algorithm and multivariate Cox regression were used to construct long-term survival predictive strategies. Multiple machine learning algorithms identified target genes for pan-cancer analysis. Lentiviral transfection created stable strains with target gene knockdown, and CCK-8 and transwell migration assays verified the target gene's effects. Western blot and flow cytometry assessed the impact of target genes on macrophage polarization. A total of 141 genes regulating macrophage polarization were identified, from which eight genes were selected to construct prognostic models. Significant differences between high-risk and low-risk groups were observed in immune cell activation, immune-related signaling pathways, and immune function. The prognostic model and target gene were validated to provide more precise immunotherapy options for osteosarcoma and other tumors. bnip3 knockdown decreased osteosarcoma cell proliferation and migration and promoted macrophage polarization to the M2 phenotype. The constructed prognostic model offers precise immunotherapy regimens and valuable insights into mechanisms underlying current studies. Furthermore, bnip3 may serve as a potential immunotherapeutic target for osteosarcoma and other tumors.

关键词： Osteosarcoma Macrophage polarization Immunotherapy Prognostic model bnip3 Tumor microenvironment

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bnip3 is essential for mitochondrial bioenergetics during adipocyte remodelling in mice

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DIABETOLOGIA 2016年第3期59卷 571-581页

作者： Choi, Jin Woo Jo, Anna Kim, Min Park, Ho Seon Chung, Sung Soo Kang, Shinae Park, Kyong Soo Seoul Natl Univ Coll Med Dept Internal Med 101 Daehak Ro Seoul 03080 South Korea Seoul Natl Univ Coll Med Dept Biomed Sci Seoul 03080 South Korea Seoul Natl Univ Grad Sch Convergence Sci & Technol Dept Mol Med & Biopharmaceut Sci Seoul 03080 South Korea Yonsei Univ Coll Med Gangnam Severance Hosp Dept Internal Med 211 Eonju Ro 146-92 Dogok Dong Seoul 135710 South Korea Yonsei Univ Coll Med Severance Inst Vasc & Metab Res Seoul 135710 South Korea

Aims/hypothesis Adipose tissue is a highly versatile system in which mitochondria in adipocytes undergo significant changes during active tissue remodelling. BCL2/adenovirus E1B 19 kDa protein-interacting protein 3 (bnip3) is a mitochondrial protein and a known mitochondrial quality regulator. In this study, we investigated the role of bnip3 in adipocytes, specifically under conditions of peroxisome proliferator-activated receptor-gamma (PPAR gamma)-induced adipose tissue remodelling. Methods The expression of bnip3 was evaluated in 3T3-L1 adipocytes in vitro, C57BL/6 mice fed a high-fat diet and db/db mice in vivo. Mitochondrial bioenergetics was investigated in bnip3-knockdown adipocytes after rosiglitazone treatment. A putative peroxisome proliferator hormone responsive element (PPRE) was characterised by promoter assay and electrophoretic mobility shift assay (EMSA). Results The protein bnip3 was more abundant in brown adipose tissue than white adipose tissue. Furthermore, bnip3 expression was upregulated by 3T3-L1 pre-adipocyte differentiation, starvation and rosiglitazone treatment. Conversely, bnip3 expression in adipocytes decreased under various conditions associated with insulin resistance. This downregulation of bnip3 was restored by rosiglitazone treatment. Knockdown of bnip3 in adipocytes inhibited rosiglitazoneinduced mitochondrial biogenesis and function, partially mediated by the 5' AMP-activated protein kinase (AMPK)-peroxisome proliferator-activated receptor gamma, co-activator 1 alpha (PGC1 alpha) signalling pathway. Rosiglitazone treatment increased the transcription level of bnip3 in the reporter assay and the presence of the PPRE site in the bnip3 promoter was demonstrated by EMSA. Conclusions/interpretation The protein bnip3 contributes to the improvement of mitochondrial bioenergetics that occurs on exposure to rosiglitazone. It may be a novel therapeutic target for restoring mitochondrial dysfunction under insulin-resistant conditions.

关键词： Adipocytes Bioenergetics bnip3 Insulin resistance Mitochondria PPRE Rosiglitazone

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Emerging role of mitophagy in heart failure: from molecular mechanism to targeted therapy

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CELL CYCLE 2023年第8期22卷 906-918页

作者： Liu, Yu Wang, Yizhou Bi, Yingfei Zhao, Zhiqiang Wang, Shuai Lin, Shanshan Yang, Zhihua Wang, Xianliang Mao, Jingyuan Tianjin Univ Tradit Chinese Med Natl Clin Res Ctr Chinese Med Acupuncture & Moxibu Teaching Hosp 1 Dept Cardiol 88 Changling Rd Tianjin 300381 Peoples R China Tianjin Acad Tradit Chinese Med Affiliated Hosp Rehabil Dept Tianjin Peoples R China

Heart failure is defined as a drop in heart's pump function, accounting for reduced blood output and venous stasis, and constitutes the end stage of various cardiovascular diseases. Although mild mitochondrial dysfunction may hinder cardiomyocyte metabolism and impair myocardial function, severe mitochondrial injury is accompanied by cardiomyocyte apoptosis, leading to irreversible damage of the heart. Selective autophagy of mitochondria, or mitophagy, serves to rapidly remove dysfunctional mitochondria and restore the health of the mitochondrial population within cells by allowing reutilization of degradative substrates such as amino acids, fatty acids, and nucleotides. Although mitophagy represents a protective program that prevents the accumulation of poorly structured or damaged mitochondria, excessive mitophagy leads to mitochondrial population decline, impaired oxidative phosphorylation, and decreased ATP production. In this review, we first discuss the molecular underpinnings of mitophagy and the roles of different mitophagy adaptors. Then, the multiple and complex influence of mitophagy on heart failure is summarized. Finally, novel pharmacological strategies targeting mitophagy to relieve heart failure are briefly summarized.

关键词： Heart failure mitophagy Parkin bnip3 FUNDC1

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Wireless, battery-free vagal electrical stimulation: A novel approach to inhibit cardiac hypertrophy via H3K18 lactylation mediated mitophagy

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PHARMACOLOGICAL RESEARCH 2025年 216卷 107760页

作者： Shi, Pilong Liu, Yang Sha, Yuetong Wang, Jiaxin Zhou, Jiajun Liu, Kai Cao, Yonggang Zhang, Qianhui Wang, Xinran Sun, Hongli Harbin Med Univ Dept Pharmacol Heilongjiang 163319 Peoples R China Harbin Med Univ Dept Basic Nursing Heilongjiang 163319 Peoples R China

Electrical stimulation (ES) has been established as a reliable and beneficial approach in therapeutic rehabilitation, exhibiting negligible side effects. Nevertheless, research focusing on the application of ES for cardiac hypertrophy remains limited, as it fails to provide an enduring remedy for chronic diseases. In this investigation, vagal ES, characterized by its wireless, battery-free, and fully implantable nature, was utilized to treat cardiac hypertrophy. The vagus nerve at the stimulation site was carefully embedded within an envelope, sealed securely using multiple bioabsorbable sutures. Subsequently, a cardiac hypertrophy model was induced in rats via abdominal aortic coarctation for four weeks. The findings of this investigation demonstrated that ES markedly attenuated cardiac hypertrophy. Metabolomic analysis revealed a notable reduction in lactate levels within myocardial tissue following ES. Proteomic analysis of myocardial tissues indicated a substantial decrease in the expression of autophagy and mitophagy-related proteins after ES. Additionally, ChIP-seq result revealed a specific binding interaction between H3K18 lactylation (H3K18la) and BCL2 interacting protein 3 (bnip3), while luciferase reporter assays demonstrated that H3K18la directly governed bnip3 transcriptional activation, exploring its role in modulating mitophagy. Mechanistically, it was shown that ES reduced lactate accumulation through the upregulation of monocarboxylate transporter 4 (MCT4) by decreasing norepinephrine (NE) levels. Furthermore, ES reversed cardiac hypertrophy by diminishing H3K18la levels, thus inhibiting bnip3 protein expression. This pathway assists in diminishing cardiac hypertrophy, emphasizing the critical involvement of the afferent vagal pathway in regulating cardiac hypertrophy.

关键词： bnip3 Cardiac hypertrophy Lactate Mitophagy Vagal electrical stimulation

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