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MED1 Regulates BMP/TGF-ß in Endothelium: Implication for Pulmonary Hypertension.
Wang, Chen; Xing, Yuanming; Zhang, Jiao; He, Ming; Dong, Jianjie; Chen, Shanshan; Wu, Haoyu; Huang, Hsi-Yuan; Chou, Chih-Hung; Bai, Liang; He, Fangzhou; She, Jianqing; Su, Ailing; Wang, Youhua; Thistlethwaite, Patricia A; Huang, Hsien-Da; Yuan, Jason X-J; Yuan, Zu-Yi; Shyy, John Y-J.
Affiliation
  • Wang C; Department of Cardiology, First Affiliated Hospital of Xi'an Jiaotong University, China (C.W., Y.X., J.Z., J.D., H.W., L.B., J.S., Z.-Y.).
  • Xing Y; Cardiovascular Research Center, School of Basic Medical Sciences, Xi'an Jiaotong University Health Science Center, China (C.W., Y.X., J.Z., J.D., S.C., L.B., F.H., A.S.).
  • Zhang J; Department of Cardiology, First Affiliated Hospital of Xi'an Jiaotong University, China (C.W., Y.X., J.Z., J.D., H.W., L.B., J.S., Z.-Y.).
  • He M; Cardiovascular Research Center, School of Basic Medical Sciences, Xi'an Jiaotong University Health Science Center, China (C.W., Y.X., J.Z., J.D., S.C., L.B., F.H., A.S.).
  • Dong J; Department of Cardiology, First Affiliated Hospital of Xi'an Jiaotong University, China (C.W., Y.X., J.Z., J.D., H.W., L.B., J.S., Z.-Y.).
  • Chen S; Cardiovascular Research Center, School of Basic Medical Sciences, Xi'an Jiaotong University Health Science Center, China (C.W., Y.X., J.Z., J.D., S.C., L.B., F.H., A.S.).
  • Wu H; Division of Cardiology, Department of Medicine, University of California, San Diego, La Jolla, CA (J.Z., M.H., J.D., J.Y.-J.).
  • Huang HY; Division of Cardiology, Department of Medicine, University of California, San Diego, La Jolla, CA (J.Z., M.H., J.D., J.Y.-J.).
  • Chou CH; Department of Cardiology, First Affiliated Hospital of Xi'an Jiaotong University, China (C.W., Y.X., J.Z., J.D., H.W., L.B., J.S., Z.-Y.).
  • Bai L; Cardiovascular Research Center, School of Basic Medical Sciences, Xi'an Jiaotong University Health Science Center, China (C.W., Y.X., J.Z., J.D., S.C., L.B., F.H., A.S.).
  • He F; Division of Cardiology, Department of Medicine, University of California, San Diego, La Jolla, CA (J.Z., M.H., J.D., J.Y.-J.).
  • She J; Cardiovascular Research Center, School of Basic Medical Sciences, Xi'an Jiaotong University Health Science Center, China (C.W., Y.X., J.Z., J.D., S.C., L.B., F.H., A.S.).
  • Su A; Department of Cardiology, First Affiliated Hospital of Xi'an Jiaotong University, China (C.W., Y.X., J.Z., J.D., H.W., L.B., J.S., Z.-Y.).
  • Wang Y; Warshel Institute for Computational Biology, The Chinese University of Hong Kong-Shenzhen, Shenzhen, China (H.-Y.H., H.-D.H.).
  • Thistlethwaite PA; School of Life and Health Sciences, The Chinese University of Hong Kong-Shenzhen, Shenzhen, China (H.-Y.H., H.-D.H.).
  • Huang HD; Department of Biological Science and Technology, National Chiao Tung University, Hsinchu, Taiwan (C.-H.C.).
  • Yuan JX; Department of Cardiology, First Affiliated Hospital of Xi'an Jiaotong University, China (C.W., Y.X., J.Z., J.D., H.W., L.B., J.S., Z.-Y.).
  • Yuan ZY; Cardiovascular Research Center, School of Basic Medical Sciences, Xi'an Jiaotong University Health Science Center, China (C.W., Y.X., J.Z., J.D., S.C., L.B., F.H., A.S.).
  • Shyy JY; Department of Cardiology, First Affiliated Hospital of Xi'an Jiaotong University, China (C.W., Y.X., J.Z., J.D., H.W., L.B., J.S., Z.-Y.).
Circ Res ; 131(10): 828-841, 2022 10 28.
Article in En | MEDLINE | ID: mdl-36252121
ABSTRACT

BACKGROUND:

Dysregulated BMP (bone morphogenetic protein) or TGF-ß (transforming growth factor beta) signaling pathways are imperative in idiopathic and familial pulmonary arterial hypertension (PAH) as well as experimental pulmonary hypertension (PH) in rodent models. MED1 (mediator complex subunit 1) is a key transcriptional co-activator and KLF4 (Krüppel-like factor 4) is a master transcription factor in endothelium. However, MED1 and KLF4 epigenetic and transcriptional regulations of the BMP/TGF-ß axes in pulmonary endothelium and their dysregulations leading to PAH remain elusive. We investigate the MED1/KLF4 co-regulation of the BMP/TGF-ß axes in endothelium by studying the epigenetic regulation of BMPR2 (BMP receptor type II), ETS-related gene (ERG), and TGFBR2 (TGF-ß receptor 2) and their involvement in the PH.

METHODS:

High-throughput screening involving data from RNA-seq, MED1 ChIP-seq, H3K27ac ChIP-seq, ATAC-seq, and high-throughput chromosome conformation capture together with in silico computations were used to explore the epigenetic and transcriptional regulation of BMPR2, ERG, and TGFBR2 by MED1 and KLF4. In vitro experiments with cultured pulmonary arterial endothelial cells (ECs) and bulk assays were used to validate results from these in silico analyses. Lung tissue from patients with idiopathic PAH, animals with experimental PH, and mice with endothelial ablation of MED1 (EC-MED1-/-) were used to study the PH-protective effect of MED1.

RESULTS:

Levels of MED1 were decreased in lung tissue or pulmonary arterial endothelial cells from idiopathic PAH patients and rodent PH models. Mechanistically, MED1 acted synergistically with KLF4 to transactivate BMPR2, ERG, and TGFBR2 via chromatin remodeling and enhancer-promoter interactions. EC-MED1-/- mice showed PH susceptibility. In contrast, MED1 overexpression mitigated the PH phenotype in rodents.

CONCLUSIONS:

A homeostatic regulation of BMPR2, ERG, and TGFBR2 in ECs by MED1 synergistic with KLF4 is essential for the normal function of the pulmonary endothelium. Dysregulation of MED1 and the resulting impairment of the BMP/TGF-ß signaling is implicated in the disease progression of PAH in humans and PH in rodent models.
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Full text: 1 Collection: 01-internacional Database: MEDLINE Main subject: Pulmonary Arterial Hypertension / Hypertension, Pulmonary Type of study: Prognostic_studies Limits: Animals / Humans Language: En Journal: Circ Res Year: 2022 Document type: Article
Fulltext
Add to My VHL
Print
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PubMed Links
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Full text: 1 Collection: 01-internacional Database: MEDLINE Main subject: Pulmonary Arterial Hypertension / Hypertension, Pulmonary Type of study: Prognostic_studies Limits: Animals / Humans Language: En Journal: Circ Res Year: 2022 Document type: Article