한빛사논문
- 조회377
Heon-Woo Lee1, Takaomi Adachi2, Boryeong Pak3, Saejeong Park1, Xiaoyue Hu1, Woosoung Choi3, Piotr S. Kowalski4, C-Hong Chang1, Katharine R. Clapham5, Aram Lee1,6, Irinna Papangeli1, Jongmin Kim6, Orjin Han3, Jihwan Park3, Daniel G. Anderson4, Michael Simons1, Suk-Won Jin1,3*, Hyung J Chun1,7*
1: Yale Cardiovascular Research Center, Section of Cardiovascular Medicine, Department of Internal Medicine, Yale University School of Medicine, New Haven, CT 06511, USA
2: Meiji University of Integrative Medicine, Kyoto, Japan
3: School of Life Sciences and Cell Logistics Research Center, Gwangju Institute of Science and Technology (GIST), Gwangju, Korea
4: David H. Koch Institute for Integrative Cancer Research, Massachusetts Institute of Technology, Cambridge, MA 02142, USA
5: Division of Pulmonary and Critical Care, Brigham and Women’s Hospital, Boston, MA 02127.
6: Division of Biological Sciences, Sookmyung Women's University, Seoul 04310, Korea.
7: VA Connecticut Healthcare System, 950 Campbell Ave, 111B, West Haven, CT 06516.
*Equal contribution
*To Whom Correspondence Should be Addressed: Hyung J. Chun or Suk-Won Jin
Abstract
Aims
Components of BMP signaling have been implicated in both pathogenesis of pulmonary arterial hypertension (PAH) and endothelial-mesenchymal transition (EndoMT). In particular, the importance of BMP Type 2 Receptor (BMPR2) in these processes have been extensively analyzed. However, the contribution of BMP Type1 Receptors (BMPR1s) to the onset of PAH and EndoMT remains poorly understood. BMPR1A, one of BMPR1s, was recently implicated in the pathogenesis of PAH, and was found to be downregulated in the lungs of PAH patients, neither the downstream mechanism nor its contribution to EndoMT has been described. Therefore, we aim to delineate the role of endothelial BMPR1A in modulating EndoMT and pathogenesis of PAH.
Methods and results
We find that BMPR1A knockdown in endothelial cells (ECs) induces hallmarks of EndoMT, and deletion of endothelial Bmpr1a in adult mice (Bmpr1aiECKO) leads to development of PAH-like symptoms due to excessive EndoMT. By lineage tracing, we show that endothelial-derived smooth muscle cells are increased in endothelial Bmpr1a deleted mice. Mechanistically, we identify ZEB1 as a primary target for BMPR1A in this setting; Upon BMPR1A activation, ID2 physically interacts and sequesters ZEB1 to attenuate transcription of Tgfbr2, which in turn lowers the responses of ECs toward TGF-β stimulation and prevents excessive EndoMT. In Bmpr1aiECKO mice, administering endothelial targeting lipid nanoparticles containing siRNA against Tgfbr2 effectively ameliorate PAH, reiterating the importance of BMPR1A-ID2/ZEB1-TGFBR2 axis in modulating progression of EndoMT and pathogenesis of PAH.
Conclusions
We demonstrate that BMPR1A is key to maintain endothelial identity and to prevent excessive EndoMT. We identify BMPR1A-induced interaction between ID2 and ZEB1 is the key regulatory step for onset of EndoMT and pathogenesis of PAH. Our findings indicate that BMPR1A-ID2/ZEB1-TGFBR2 signaling axis could serve as a potential novel therapeutic target for PAH and other EndoMT-related vascular disorders.
논문정보
- Research article
- 2022년 09월 (BRIC 등록일 2022-10-07)
- 국내(교신)+국외 연구진
- 생명과학 > 유전학
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