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2015 ; 117
(4
): 364-375
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Bach1 Represses Wnt/?-Catenin Signaling and Angiogenesis
#MMPMID26123998
Jiang L
; Yin M
; Wei X
; Liu J
; Wang X
; Niu C
; Kang X
; Xu J
; Zhou Z
; Sun S
; Wang X
; Zheng X
; Duan S
; Yao K
; Qian R
; Sun N
; Chen A
; Wang R
; Zhang J
; Chen S
; Meng D
Circ Res
2015[Jul]; 117
(4
): 364-375
PMID26123998
show ga
RATIONALE: Wnt/?-catenin signaling has an important role in the angiogenic
activity of endothelial cells (ECs). Bach1 is a transcription factor and is
expressed in ECs, but whether Bach1 regulates angiogenesis is unknown. OBJECTIVE:
This study evaluated the role of Bach1 in angiogenesis and Wnt/?-catenin
signaling. METHODS AND RESULTS: Hind-limb ischemia was surgically induced in
Bach1(-/-) mice and their wild-type littermates and in C57BL/6J mice treated with
adenoviruses coding for Bach1 or GFP. Lack of Bach1 expression was associated
with significant increases in perfusion and vascular density and in the
expression of proangiogenic cytokines in the ischemic hindlimb of mice, with
enhancement of the angiogenic activity of ECs (eg, tube formation, migration, and
proliferation). Bach1 overexpression impaired angiogenesis in mice with hind-limb
ischemia and inhibited Wnt3a-stimulated angiogenic response and the expression of
Wnt/?-catenin target genes, such as interleukin-8 and vascular endothelial growth
factor, in human umbilical vein ECs. Interleukin-8 and vascular endothelial
growth factor were responsible for the antiangiogenic response of Bach1.
Immunoprecipitation and GST pull-down assessments indicated that Bach1 binds
directly to TCF4 and reduces the interaction of ?-catenin with TCF4. Bach1
overexpression reduces the interaction between p300/CBP and ?-catenin, as well as
?-catenin acetylation, and chromatin immunoprecipitation experiments confirmed
that Bach1 occupies the TCF4-binding site of the interleukin-8 promoter and
recruits histone deacetylase 1 to the interleukin-8 promoter in human umbilical
vein ECs. CONCLUSIONS: Bach1 suppresses angiogenesis after ischemic injury and
impairs Wnt/?-catenin signaling by disrupting the interaction between ?-catenin
and TCF4 and by recruiting histone deacetylase 1 to the promoter of TCF4-targeted
genes.