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Gewählte Publikation:
SHR Neuro Krebs Kardio Lipid Stoffw Microb
Lin, J; Liu, X; Li, Q; Ge, F; Ma, J; Ng, X; Pan, Q; Wei, X; Jiang, Q; Jin, J; Ma, S; He, Y; Li, Y; Jiang, N; Hou, Y; Yu, Y; Lin, X; Jin, Q; Xu, C; Wang, X; Zhi, X; Liang, Q; Jiang, L; Osto, E; Guo, J; Wang, XJ; Meng, D.
A BACH1 Inhibitor Ameliorates Myocardial Infarction and Limb Ischemia in Mice.
Mol Ther. 2025;
Doi: 10.1016/j.ymthe.2025.07.008
PubMed
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- Co-Autor*innen der Med Uni Graz
- Osto Elena
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- 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.