A BACH1 Inhibitor Ameliorates Myocardial Infarction and Limb Ischemia in Mice.

IF 12.1 1区医学 Q1 BIOTECHNOLOGY & APPLIED MICROBIOLOGY

Molecular Therapy Pub Date : 2025-07-16 DOI:10.1016/j.ymthe.2025.07.008

Jiayi Lin,Xin Liu,Qinhan Li,Fei Ge,Jinghua Ma,Xianlong Ng,Qi Pan,Xiangxiang Wei,Qingjun Jiang,Jiayu Jin,Siyu Ma,Yunquan He,Yongbo Li,Nan Jiang,Yannan Hou,Yueyang Yu,Xiaoke Lin,Quanshan Jin,Chengguo Xu,Xinhong Wang,Xiuling Zhi,Qianqian Liang,Lindi Jiang,Elena Osto,Jieyu Guo,Xiu-Jie Wang,Dan Meng

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引用次数: 0

Abstract

The transcription factor BTB and CNC homology 1 (BACH1) is linked to coronary artery disease risk and impairs angiogenesis after ischemic injury. However, there is a scarcity of specific BACH1 inhibitors. This study identifies BI033 as a selective BACH1 inhibitor, confirming its binding to the 91st alanine in BACH1's N-terminal. BI033 shows lower toxicity in human umbilical vein endothelial cells (HUVECs) than the BACH1 inhibitor, HPPE. Intraperitoneal BI033 injections in mice enhance vascular density in the infarct border zone, reduce scar size, and ameliorate contractile dysfunction post-myocardial infarction (MI). Intramuscular injections of BI033 in the ischemic hindlimbs of mice also enhance perfusion and vascular density in the ischemic tissue. Mechanistically, BI033 decreases BACH1's nuclear localization and the enrichment of its target genes like heme oxygenase-1 (HO-1) and vascular endothelial growth factor A (VEGFA), while enhancing Nuclear Factor Erythroid 2-Related Factor 2 (NRF2)'s nuclear accumulation and its enrichment of target genes in HUVECs. Additionally, BI033 reduces BACH1-Histone Deacetylase 1 (HDAC1) interaction, elevating the enrichment of the histone 3 lysine 27 acetylation (H3K27ac) at BACH1 target genes, leading to increased expression of angiogenic-related genes. Thus, the BACH1 inhibitor BI033 could serve as a therapy for MI and peripheral ischemic vascular disease.

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一种BACH1抑制剂改善小鼠心肌梗死和肢体缺血。

转录因子BTB和CNC同源物1 （BACH1）与缺血性损伤后冠状动脉疾病风险和损害血管生成有关。然而，特异性BACH1抑制剂缺乏。本研究发现BI033是一种选择性的BACH1抑制剂，证实其与BACH1 n端第91个丙氨酸结合。BI033对人脐静脉内皮细胞（HUVECs）的毒性低于BACH1抑制剂HPPE。小鼠腹腔注射BI033可增强梗死边界区血管密度，减小瘢痕大小，改善心肌梗死后收缩功能障碍。在小鼠缺血后肢肌内注射BI033也能增强缺血组织的灌注和血管密度。在机制上，BI033降低了BACH1的核定位及其靶基因血红素加氧酶-1 （HO-1）和血管内皮生长因子A （VEGFA）的富集，同时增强了核因子红系2相关因子2 （NRF2）在HUVECs中的核积累及其靶基因的富集。此外，BI033降低BACH1- histone Deacetylase 1 （HDAC1）相互作用，提高BACH1靶基因上组蛋白3赖氨酸27乙酰化（H3K27ac）的富集，导致血管生成相关基因的表达增加。因此，BACH1抑制剂BI033可作为心肌梗死和周围缺血性血管疾病的治疗药物。

本文章由计算机程序翻译，如有差异，请以英文原文为准。

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来源期刊

Molecular Therapy 医学-生物工程与应用微生物

CiteScore

19.20

自引率

3.20%

发文量

357

审稿时长

3 months

期刊介绍： Molecular Therapy is the leading journal for research in gene transfer, vector development, stem cell manipulation, and therapeutic interventions. It covers a broad spectrum of topics including genetic and acquired disease correction, vaccine development, pre-clinical validation, safety/efficacy studies, and clinical trials. With a focus on advancing genetics, medicine, and biotechnology, Molecular Therapy publishes peer-reviewed research, reviews, and commentaries to showcase the latest advancements in the field. With an impressive impact factor of 12.4 in 2022, it continues to attract top-tier contributions.