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Published on: February 20, 2019
Deletion of BACH1 Attenuates Atherosclerosis by Reducing Endothelial Inflammation
Mengping Jia1,2, Qinhan Li1, Jieyu Guo1
1Department of Physiology and Pathophysiology, School of Basic Medical Sciences, Shanghai Key Laboratory of Vascular Lesions Regulation and Remodeling (M.J., Q.L., J.G., Y.L., S.M., T.Z., Q.P., X. Wei., Y.Q., X.L., J.J., X.Z., Xinhong Wang, D.M.).
Insights
The transcription factor BACH1 is crucial in atherosclerosis development by regulating vascular inflammation and plaque formation. Targeting BACH1 offers a potential new therapeutic strategy for treating atherosclerosis.
Area of Science:
- Vascular Biology
- Cardiovascular Research
- Molecular Medicine
Background:
- The transcription factor BACH1 (BTB and CNC homology 1) is known to affect endothelial cell proliferation, migration, and angiogenesis.
- Its specific role and underlying mechanisms in atherosclerosis, a complex vascular disease, remained largely uncharacterized.
Purpose of the Study:
- To investigate the role of BACH1 in the regulation of atherogenesis.
- To elucidate the underlying molecular mechanisms of BACH1 in the context of atherosclerosis.
Main Methods:
- Utilized endothelial cell (EC)-specific Bach1 knockout mouse models to study atherogenesis.
- Performed genetic analyses on human carotid plaques and analyzed BACH1 expression in human and mouse atherosclerotic lesions.
- Investigated BACH1's interaction with YAP (yes-associated protein) and its role in endothelial cell responses to shear stress and inflammatory stimuli.
- Assessed the effect of rosuvastatin on BACH1 expression.
Main Results:
- BACH1 was upregulated in atherosclerotic ECs, and its deficiency reduced lesion development, macrophage content, and adhesion molecule expression (ICAM1, VCAM1).
- Endothelial Bach1 deficiency decreased pro-inflammatory cytokines (TNF-α, IL-1β) and inhibited monocyte-endothelial adhesion.
- BACH1 forms a complex with YAP, promoting the transcription of adhesion molecules, and this BACH1-YAP network is activated by hemodynamic stress and TNF-α.
- Rosuvastatin reduced BACH1 expression in hyperlipidemic mice.
Conclusions:
- Identified BACH1 as a key mechanosensor of hemodynamic stress in the vasculature.
- The BACH1-YAP transcriptional network is essential for vascular inflammation and the development of atherosclerosis.
- BACH1 represents a promising novel therapeutic target for atherosclerosis treatment.
Background:
The transcription factor BACH1 (BTB and CNC homology 1) suppressed endothelial cells (ECs) proliferation and migration and impaired angiogenesis in the ischemic hindlimbs of adult mice. However, the role and underlying mechanisms of BACH1 in atherosclerosis remain unclear.
Methods:
Mouse models of atherosclerosis in endothelial cell (EC)-specific-Bach1 knockout mice were used to study the role of BACH1 in the regulation of atherogenesis and the underlying mechanisms.
Results:
Genetic analyses revealed that coronary artery disease-associated risk variant rs2832227 was associated with BACH1 gene expression in carotid plaques from patients. BACH1 was upregulated in ECs of human and mouse atherosclerotic plaques. Endothelial Bach1 deficiency decreased turbulent blood flow- or western diet-induced atherosclerotic lesions, macrophage content in plaques, expression of endothelial adhesion molecules (ICAM1 [intercellular cell adhesion molecule-1] and VCAM1 [vascular cell adhesion molecule-1]), and reduced plasma TNF-α (tumor necrosis factor-α) and IL-1β levels in atherosclerotic mice. BACH1 deletion or knockdown inhibited monocyte-endothelial adhesion and reduced oscillatory shear stress or TNF-α-mediated induction of endothelial adhesion molecules and/or proinflammatory cytokines in mouse ECs, human umbilical vein ECs, and human aortic ECs. Mechanistic studies showed that upon oscillatory shear stress or TNF-α stimulation, BACH1 and YAP (yes-associated protein) were induced and translocated into the nucleus in ECs. BACH1 upregulated YAP expression by binding to the YAP promoter. BACH1 formed a complex with YAP inducing the transcription of adhesion molecules. YAP overexpression in ECs counteracted the antiatherosclerotic effect mediated by Bach1-deletion in mice. Rosuvastatin inhibited BACH1 expression by upregulating microRNA let-7a in ECs, and decreased Bach1 expression in the vascular endothelium of hyperlipidemic mice. BACH1 was colocalized with YAP, and the expression of BACH1 was positively correlated with YAP and proinflammatory genes, as well as adhesion molecules in human atherosclerotic plaques.
Conclusions:
These data identify BACH1 as a mechanosensor of hemodynamic stress and reveal that the BACH1-YAP transcriptional network is essential to vascular inflammation and atherogenesis. BACH1 shows potential as a novel therapeutic target in atherosclerosis.
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