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Deletion of BACH1 Attenuates Atherosclerosis by Reducing Endothelial Inflammation.
Jia, Mengping; Li, Qinhan; Guo, Jieyu; Shi, Weihao; Zhu, Lei; Huang, Yijun; Li, Yongbo; Wang, Li; Ma, Siyu; Zhuang, Tao; Wang, Xiaoqun; Pan, Qi; Wei, Xiangxiang; Qin, Yue; Li, Xiaobo; Jin, Jiayu; Zhi, Xiuling; Tang, Jingdong; Jing, Qing; Li, Shanqun; Jiang, Lindi; Qu, Lefeng; Osto, Elena; Zhang, Jianyi; Wang, Xinhong; Yu, Bo; Meng, Dan.
Afiliação
  • Jia M; Department 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.).
  • Li Q; Department of Pulmonary Medicine, Zhongshan Hospital (M.J., S.L.,), Fudan University, Shanghai, China.
  • Guo J; Department 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.).
  • Shi W; Department 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.).
  • Zhu L; Vascular Service, Department of General Surgery, Huashan Hospital (W.S., L.Z., Y.H., B.Y.), Fudan University, Shanghai, China.
  • Huang Y; Vascular Service, Department of General Surgery, Huashan Hospital (W.S., L.Z., Y.H., B.Y.), Fudan University, Shanghai, China.
  • Li Y; Vascular Service, Department of General Surgery, Huashan Hospital (W.S., L.Z., Y.H., B.Y.), Fudan University, Shanghai, China.
  • Wang L; Department 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.).
  • Ma S; Department of Biomedical Sciences, City University of Hong Kong, China (L.W.).
  • Zhuang T; Department 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.).
  • Wang X; Department 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.).
  • Pan Q; Department of Cardiology, Ruijin Hospital, Shanghai Jiao Tong University School of Medicine, China (Xiaoqun Wang.).
  • Wei X; Department 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.).
  • Qin Y; Department 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.).
  • Li X; Department 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.).
  • Jin J; Department 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.).
  • Zhi X; Department 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.).
  • Tang J; Department 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.).
  • Jing Q; Department of General Surgery, Shanghai Pudong Hospital, Shanghai Key Laboratory of Vascular Lesions Regulation and Remodeling, China (J.T., B.Y.).
  • Li S; CAS Key Laboratory of Tissue Microenvironment and Tumor, Shanghai Institute of Nutrition and Health, Innovation Center for Intervention of Chronic Disease and Promotion of Health, University of Chinese Academy of Sciences, Chinese Academy of Sciences, China (Q.J.).
  • Jiang L; Department of Pulmonary Medicine, Zhongshan Hospital (M.J., S.L.,), Fudan University, Shanghai, China.
  • Qu L; Department of Rheumatology, Zhongshan Hospital (L.J., D.M.), Fudan University, Shanghai, China.
  • Osto E; Department of Vascular and Endovascular Surgery, Changzheng Hospital, Naval Medical University, Shanghai, China (L.Q.).
  • Zhang J; Institute of Clinical Chemistry and Department of Cardiology, University Heart Center, University and University Hospital Zurich, Switzerland (E.O.).
  • Wang X; Department of Biomedical Engineering, University of Alabama at Birmingham (J.Z.).
  • Yu B; Department 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.).
  • Meng D; Vascular Service, Department of General Surgery, Huashan Hospital (W.S., L.Z., Y.H., B.Y.), Fudan University, Shanghai, China.
Circ Res ; 130(7): 1038-1055, 2022 04.
Article em En | MEDLINE | ID: mdl-35196865
ABSTRACT

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-1ß 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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Texto completo: 1 Base de dados: MEDLINE Assunto principal: Aterosclerose / Placa Aterosclerótica Tipo de estudo: Prognostic_studies Limite: Animals / Humans Idioma: En Ano de publicação: 2022 Tipo de documento: Article
Texto completo
Imprimir
XML
PubMed Links
Buscar no Google

Texto completo: 1 Base de dados: MEDLINE Assunto principal: Aterosclerose / Placa Aterosclerótica Tipo de estudo: Prognostic_studies Limite: Animals / Humans Idioma: En Ano de publicação: 2022 Tipo de documento: Article