Bach1-induced suppression of angiogenesis is dependent on the BTB domain

Abstract

The transcription factor Bach1 impairs angiogenesis after ischemic injury by suppressing Wnt/b-catenin signaling; however, the specific domains responsible for the anti-angiogenic effects of Bach1 remain unclear. This study determined the role of the BTB domain of Bach1 in ischemic angiogenesis. Bach1 is highly expressed in circulating endothelial cells from acute myocardial infarction patients and is the early induction gene after ischemia. Mice were treated with adenoviruses coding for GFP (AdGFP), Bach1 (AdBach1), or a Bach1 mutant lacking the BTB domain (AdBach1-DBTB) after surgically induced hind-limb ischemia. Measures of blood-flow recovery, capillary density, and the expression of vascular endothelial growth factor (VEGF) and heme oxygenase-1 (HO-1) were significantly lower and ROS levels were higher in the AdBach1 group, but not in AdBach1-DBTB animals. Furthermore, transfection with AdBach1, but not AdBach1-DBTB, in human endothelial cells was associated with significant declines in 1) capillary density and hemoglobin content in the Matrigel-plug assay, 2) proliferation, migration, tube formation, and VEGF and HO-1 expression in endothelial cells. Bach1 binds directly with TCF4, and this interaction is mediated by residues 81À89 of the Bach1 BTB domain and the N-terminal domain of TCF4. Bach1, but not Bach1-DBTB, also co-precipitated with histone deacetylase 1 (HDAC1), while the full-length HDAC1 proteins, but not HDAC1 mutants lacking the protein-interaction domain, co-precipitated with Bach1. Collectively, these results demonstrate that the anti-angiogenic activity of Bach1 is crucially dependent on molecular interactions that are mediated by the protein's BTB domain, and this domain could be a drug target for angiogenic therapy.

A Morphomolecular Approach to Alveolar Capillary Dysplasia

“…TCF4 serves as a binding partner for BTB domain and CNC Q24 homolog 1, and their binding results in blockage of Wnt-targeted promoter activity and VEGF gene expression. 41 In this study, we found increased expression of PTK7, ROR2, and TCF4, suggesting a prominent role of Wnt and VEGF signaling in the pathophysiology of ACD/MPV. However, we could not corroborate these findings on the protein level as Wnt10b and VEGFR1 showed the same expression level and specificity in ACD, PAH, and healthy control lungs.…”

Signal amplification in the KEAP1-NRF2-ARE antioxidant response pathway

“…Using siRNA to silence BACH1, it was demonstrated in Huh-7 hepatocytes that both the basal and heme-stimulated HO-1 expression can be upregulated [ 92 ]. But unlike sMaf, which does not have a domain to recruit corepressors and thus in its homodimeric form can function only as passive repressors by occupying cognate MAREs [ 93 ], BACH1 has a corepressor-recruiting domain and can function as an active transcriptional repressor [ 94 ].…”

Brain‐targeting drug delivery systems

“…As brain tumor lesions expand, BTB acquires distinct properties in the tumor core compared with the peritumoral and neural parenchyma and exhibit higher leakage. BBB disruption is the result of increased vascular endothelial growth factor expression and angiogenesis in the hypoxic core which caused by the activation of hypoxia inducible factor‐1α (HIF‐1α) signaling pathway (Jiang et al, 2020). In order to maintain the high metabolic demand of tumor cells, GLUT‐1 which is responsible for passive glucose transport, and L‐type amino transporters 1 (LAT1) that maintains the bidirectional transport of neutral amino acids, are highly expressed on BTB (Bhattacharya et al, 2019; Zhang, Chen, Shi, et al, 2021).…”