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已发表论文
P300 目标乙酰化组揭示了心肌梗死后 HMGB1 转位在中枢心脏交感神经激活中的作用
Authors Yin J, Liu F, Xia H, Yan S, Wang Y, Li X, Shi Y, Wang Y, Jing Y, Li Y , Hu H
Received 22 February 2025
Accepted for publication 10 September 2025
Published 4 November 2025 Volume 2025:18 Pages 15329—15347
DOI https://doi.org/10.2147/JIR.S524375
Checked for plagiarism Yes
Review by Single anonymous peer review
Peer reviewer comments 3
Editor who approved publication: Dr Qing Lin
Jie Yin,1,2,* Fuhong Liu,2,3,* Huitang Xia,4 Suhua Yan,2 Ye Wang,2 Xinran Li,2 Yugen Shi,2 Yu Wang,2 Yanyan Jing,5 Yan Li,3,6 Hesheng Hu2
1Department of Cardiology, Shandong Provincial Hospital affiliated with Shandong First Medical University, Jinan, Shandong, People’s Republic of China; 2Department of Cardiology, the First Affiliated Hospital of Shandong First Medical University & Shandong Provincial Qianfoshan Hospital, Jinan, Shandong, People’s Republic of China; 3Medical Research Center, the First Affiliated Hospital of Shandong First Medical University & Shandong Provincial Qianfoshan Hospital, Jinan, Shandong, People’s Republic of China; 4Department of Plastic Surgery, the First Affiliated Hospital of Shandong First Medical University and Shandong Provincial Qianfoshan Hospital, Jinan, Shandong, People’s Republic of China; 5Department of Cardiology, Yantai Yuhuangding Hospital, Yantai, Shandong, People’s Republic of China; 6Shandong Province University Clinical Immunology Translational Medicine Laboratory, The First Afffliated Hospital of Shandong First Medical University and Shandong Provincial Qianfoshan Hospital, Jinan, Shandong, People’s Republic of China
*These authors contributed equally to this work
Correspondence: Hesheng Hu, Email huhesheng@sfdmu.edu.cn Yan Li, Email yli@email.sdfmu.edu.cn
Background: Microglia/macrophage-dominated neuroinflammation in the hypothalamic paraventricular nucleus (PVN) critically mediates sympathetic overactivation, with the underlying mechanism remained elusive. Given that protein acetylation serves as a pivotal epigenetic modifier of inflammatory responses to immune-microenvironmental changes, we aimed to explore the role of acetyltransferase p300 in the pathophysiological process of sympathetic activation post-myocardial infarction (MI).
Methods and Results: Rats MI model was established by ligating LAD artery. During early stage, p300 was increased in the PVN and mainly localized on microglia. Microinjection of short-hairpin RNA (shRNA) targeting p300 into the PVN effectively knocked down p300 expression, resulting in reduced peripheral sympathetic nerve activity and decreased cardiac norepinephrine levels. Programmed electrical stimulation post-MI revealed that p300 knockdown decreased ventricular arrhythmia (VA) susceptibility. p300-regulated acetylome was analyzed using shotgun proteomics in human HCM3 cells, and 135 target acetylated proteins were identified. Bioinformatic analysis and coimmunoprecipitation assays revealed that p300 interacted with and acetylated high-mobility group protein B1 (HMGB1). P300 facilitated the cytoplasmic translocation of HMGB in microglia in vivo, thereby contributing to cardiac sympathetic activation. Protein docking analysis and brain slice patch-clamp recordings revealed the potential interaction between HMGB1 and excitatory glutamate receptor N-methyl-D-aspartate receptor (NMDAR) levels. Rescue experiments employing patch-clamp electrophysiology with a recepor-specific inhibitor confirmed direct mediation of HMGB1 in neuronal activation through NMDAR-dependent mechanisms.
Conclusion: Microglial p300-mediated translocation of HMGB1 in the PVN may be a fundamental epigenetic mechanism in NMDAR-mediated central sympathetic activation post-MI, suggesting targeting p300 signaling modulation in the PVN as a potential antiarrhythmic therapy.
Keywords: acetylation, p300, myocardial infarction, paraventricular nucleus, sympathetic activation
1Department of Cardiology, Shandong Provincial Hospital affiliated with Shandong First Medical University, Jinan, Shandong, People’s Republic of China; 2Department of Cardiology, the First Affiliated Hospital of Shandong First Medical University & Shandong Provincial Qianfoshan Hospital, Jinan, Shandong, People’s Republic of China; 3Medical Research Center, the First Affiliated Hospital of Shandong First Medical University & Shandong Provincial Qianfoshan Hospital, Jinan, Shandong, People’s Republic of China; 4Department of Plastic Surgery, the First Affiliated Hospital of Shandong First Medical University and Shandong Provincial Qianfoshan Hospital, Jinan, Shandong, People’s Republic of China; 5Department of Cardiology, Yantai Yuhuangding Hospital, Yantai, Shandong, People’s Republic of China; 6Shandong Province University Clinical Immunology Translational Medicine Laboratory, The First Afffliated Hospital of Shandong First Medical University and Shandong Provincial Qianfoshan Hospital, Jinan, Shandong, People’s Republic of China
*These authors contributed equally to this work
Correspondence: Hesheng Hu, Email huhesheng@sfdmu.edu.cn Yan Li, Email yli@email.sdfmu.edu.cn
Background: Microglia/macrophage-dominated neuroinflammation in the hypothalamic paraventricular nucleus (PVN) critically mediates sympathetic overactivation, with the underlying mechanism remained elusive. Given that protein acetylation serves as a pivotal epigenetic modifier of inflammatory responses to immune-microenvironmental changes, we aimed to explore the role of acetyltransferase p300 in the pathophysiological process of sympathetic activation post-myocardial infarction (MI).
Methods and Results: Rats MI model was established by ligating LAD artery. During early stage, p300 was increased in the PVN and mainly localized on microglia. Microinjection of short-hairpin RNA (shRNA) targeting p300 into the PVN effectively knocked down p300 expression, resulting in reduced peripheral sympathetic nerve activity and decreased cardiac norepinephrine levels. Programmed electrical stimulation post-MI revealed that p300 knockdown decreased ventricular arrhythmia (VA) susceptibility. p300-regulated acetylome was analyzed using shotgun proteomics in human HCM3 cells, and 135 target acetylated proteins were identified. Bioinformatic analysis and coimmunoprecipitation assays revealed that p300 interacted with and acetylated high-mobility group protein B1 (HMGB1). P300 facilitated the cytoplasmic translocation of HMGB in microglia in vivo, thereby contributing to cardiac sympathetic activation. Protein docking analysis and brain slice patch-clamp recordings revealed the potential interaction between HMGB1 and excitatory glutamate receptor N-methyl-D-aspartate receptor (NMDAR) levels. Rescue experiments employing patch-clamp electrophysiology with a recepor-specific inhibitor confirmed direct mediation of HMGB1 in neuronal activation through NMDAR-dependent mechanisms.
Conclusion: Microglial p300-mediated translocation of HMGB1 in the PVN may be a fundamental epigenetic mechanism in NMDAR-mediated central sympathetic activation post-MI, suggesting targeting p300 signaling modulation in the PVN as a potential antiarrhythmic therapy.
Keywords: acetylation, p300, myocardial infarction, paraventricular nucleus, sympathetic activation