Cargando…
Rieske iron-sulfur protein induces FKBP12.6/RyR2 complex remodeling and subsequent pulmonary hypertension through NF-κB/cyclin D1 pathway
Ca(2+) signaling in pulmonary arterial smooth muscle cells (PASMCs) plays an important role in pulmonary hypertension (PH). However, the underlying specific ion channel mechanisms remain largely unknown. Here, we report ryanodine receptor (RyR) channel activity and Ca(2+) release both are increased,...
Autores principales: | , , , , , , , , , , |
---|---|
Formato: | Online Artículo Texto |
Lenguaje: | English |
Publicado: |
Nature Publishing Group UK
2020
|
Materias: | |
Acceso en línea: | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7363799/ https://www.ncbi.nlm.nih.gov/pubmed/32669538 http://dx.doi.org/10.1038/s41467-020-17314-1 |
_version_ | 1783559710190862336 |
---|---|
author | Mei, Lin Zheng, Yun-Min Song, Tengyao Yadav, Vishal R. Joseph, Leroy C. Truong, Lillian Kandhi, Sharath Barroso, Margarida M. Takeshima, Hiroshi Judson, Marc A. Wang, Yong-Xiao |
author_facet | Mei, Lin Zheng, Yun-Min Song, Tengyao Yadav, Vishal R. Joseph, Leroy C. Truong, Lillian Kandhi, Sharath Barroso, Margarida M. Takeshima, Hiroshi Judson, Marc A. Wang, Yong-Xiao |
author_sort | Mei, Lin |
collection | PubMed |
description | Ca(2+) signaling in pulmonary arterial smooth muscle cells (PASMCs) plays an important role in pulmonary hypertension (PH). However, the underlying specific ion channel mechanisms remain largely unknown. Here, we report ryanodine receptor (RyR) channel activity and Ca(2+) release both are increased, and association of RyR2 by FK506 binding protein 12.6 (FKBP12.6) is decreased in PASMCs from mice with chronic hypoxia (CH)-induced PH. Smooth muscle cell (SMC)-specific RyR2 knockout (KO) or Rieske iron-sulfur protein (RISP) knockdown inhibits the altered Ca(2+) signaling, increased nuclear factor (NF)-κB/cyclin D1 activation and cell proliferation, and CH-induced PH in mice. FKBP12.6 KO or FK506 treatment enhances CH-induced PH, while S107 (a specific stabilizer of RyR2/FKBP12.6 complex) produces an opposite effect. In conclusion, CH causes RISP-dependent ROS generation and FKBP12.6/RyR2 dissociation, leading to PH. RISP inhibition, RyR2/FKBP12.6 complex stabilization and Ca(2+) release blockade may be potentially beneficial for the treatment of PH. |
format | Online Article Text |
id | pubmed-7363799 |
institution | National Center for Biotechnology Information |
language | English |
publishDate | 2020 |
publisher | Nature Publishing Group UK |
record_format | MEDLINE/PubMed |
spelling | pubmed-73637992020-07-20 Rieske iron-sulfur protein induces FKBP12.6/RyR2 complex remodeling and subsequent pulmonary hypertension through NF-κB/cyclin D1 pathway Mei, Lin Zheng, Yun-Min Song, Tengyao Yadav, Vishal R. Joseph, Leroy C. Truong, Lillian Kandhi, Sharath Barroso, Margarida M. Takeshima, Hiroshi Judson, Marc A. Wang, Yong-Xiao Nat Commun Article Ca(2+) signaling in pulmonary arterial smooth muscle cells (PASMCs) plays an important role in pulmonary hypertension (PH). However, the underlying specific ion channel mechanisms remain largely unknown. Here, we report ryanodine receptor (RyR) channel activity and Ca(2+) release both are increased, and association of RyR2 by FK506 binding protein 12.6 (FKBP12.6) is decreased in PASMCs from mice with chronic hypoxia (CH)-induced PH. Smooth muscle cell (SMC)-specific RyR2 knockout (KO) or Rieske iron-sulfur protein (RISP) knockdown inhibits the altered Ca(2+) signaling, increased nuclear factor (NF)-κB/cyclin D1 activation and cell proliferation, and CH-induced PH in mice. FKBP12.6 KO or FK506 treatment enhances CH-induced PH, while S107 (a specific stabilizer of RyR2/FKBP12.6 complex) produces an opposite effect. In conclusion, CH causes RISP-dependent ROS generation and FKBP12.6/RyR2 dissociation, leading to PH. RISP inhibition, RyR2/FKBP12.6 complex stabilization and Ca(2+) release blockade may be potentially beneficial for the treatment of PH. Nature Publishing Group UK 2020-07-15 /pmc/articles/PMC7363799/ /pubmed/32669538 http://dx.doi.org/10.1038/s41467-020-17314-1 Text en © The Author(s) 2020 Open Access This article is licensed under a Creative Commons Attribution 4.0 International License, which permits use, sharing, adaptation, distribution and reproduction in any medium or format, as long as you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons license, and indicate if changes were made. The images or other third party material in this article are included in the article’s Creative Commons license, unless indicated otherwise in a credit line to the material. If material is not included in the article’s Creative Commons license and your intended use is not permitted by statutory regulation or exceeds the permitted use, you will need to obtain permission directly from the copyright holder. To view a copy of this license, visit http://creativecommons.org/licenses/by/4.0/. |
spellingShingle | Article Mei, Lin Zheng, Yun-Min Song, Tengyao Yadav, Vishal R. Joseph, Leroy C. Truong, Lillian Kandhi, Sharath Barroso, Margarida M. Takeshima, Hiroshi Judson, Marc A. Wang, Yong-Xiao Rieske iron-sulfur protein induces FKBP12.6/RyR2 complex remodeling and subsequent pulmonary hypertension through NF-κB/cyclin D1 pathway |
title | Rieske iron-sulfur protein induces FKBP12.6/RyR2 complex remodeling and subsequent pulmonary hypertension through NF-κB/cyclin D1 pathway |
title_full | Rieske iron-sulfur protein induces FKBP12.6/RyR2 complex remodeling and subsequent pulmonary hypertension through NF-κB/cyclin D1 pathway |
title_fullStr | Rieske iron-sulfur protein induces FKBP12.6/RyR2 complex remodeling and subsequent pulmonary hypertension through NF-κB/cyclin D1 pathway |
title_full_unstemmed | Rieske iron-sulfur protein induces FKBP12.6/RyR2 complex remodeling and subsequent pulmonary hypertension through NF-κB/cyclin D1 pathway |
title_short | Rieske iron-sulfur protein induces FKBP12.6/RyR2 complex remodeling and subsequent pulmonary hypertension through NF-κB/cyclin D1 pathway |
title_sort | rieske iron-sulfur protein induces fkbp12.6/ryr2 complex remodeling and subsequent pulmonary hypertension through nf-κb/cyclin d1 pathway |
topic | Article |
url | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7363799/ https://www.ncbi.nlm.nih.gov/pubmed/32669538 http://dx.doi.org/10.1038/s41467-020-17314-1 |
work_keys_str_mv | AT meilin rieskeironsulfurproteininducesfkbp126ryr2complexremodelingandsubsequentpulmonaryhypertensionthroughnfkbcyclind1pathway AT zhengyunmin rieskeironsulfurproteininducesfkbp126ryr2complexremodelingandsubsequentpulmonaryhypertensionthroughnfkbcyclind1pathway AT songtengyao rieskeironsulfurproteininducesfkbp126ryr2complexremodelingandsubsequentpulmonaryhypertensionthroughnfkbcyclind1pathway AT yadavvishalr rieskeironsulfurproteininducesfkbp126ryr2complexremodelingandsubsequentpulmonaryhypertensionthroughnfkbcyclind1pathway AT josephleroyc rieskeironsulfurproteininducesfkbp126ryr2complexremodelingandsubsequentpulmonaryhypertensionthroughnfkbcyclind1pathway AT truonglillian rieskeironsulfurproteininducesfkbp126ryr2complexremodelingandsubsequentpulmonaryhypertensionthroughnfkbcyclind1pathway AT kandhisharath rieskeironsulfurproteininducesfkbp126ryr2complexremodelingandsubsequentpulmonaryhypertensionthroughnfkbcyclind1pathway AT barrosomargaridam rieskeironsulfurproteininducesfkbp126ryr2complexremodelingandsubsequentpulmonaryhypertensionthroughnfkbcyclind1pathway AT takeshimahiroshi rieskeironsulfurproteininducesfkbp126ryr2complexremodelingandsubsequentpulmonaryhypertensionthroughnfkbcyclind1pathway AT judsonmarca rieskeironsulfurproteininducesfkbp126ryr2complexremodelingandsubsequentpulmonaryhypertensionthroughnfkbcyclind1pathway AT wangyongxiao rieskeironsulfurproteininducesfkbp126ryr2complexremodelingandsubsequentpulmonaryhypertensionthroughnfkbcyclind1pathway |