Rieske iron-sulfur protein induces FKBP12.6/RyR2 complex remodeling and subsequent pulmonary hypertension through NF-κB/cyclin D1 pathway

Lin Mei, Yun-Min Zheng, Tengyao Song, Vishal R. Yadav, Leroy C. Joseph, Lillian Truong, Sharath Kandhi, Margarida M. Barroso, Hiroshi Takeshima, Marc A. Judson and Yong-Xiao Wang ()
Additional contact information
Lin Mei: Albany Medical College
Yun-Min Zheng: Albany Medical College
Tengyao Song: Albany Medical College
Vishal R. Yadav: Albany Medical College
Leroy C. Joseph: Albany Medical College
Lillian Truong: Albany Medical College
Sharath Kandhi: Albany Medical College
Margarida M. Barroso: Albany Medical College
Hiroshi Takeshima: Kyoto University Graduate School of Pharmaceutical Sciences
Marc A. Judson: Albany Medical College
Yong-Xiao Wang: Albany Medical College

Nature Communications, 2020, vol. 11, issue 1, 1-14

Abstract: Abstract Ca2+ 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 Ca2+ 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 Ca2+ 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 Ca2+ release blockade may be potentially beneficial for the treatment of PH.

Date: 2020
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DOI: 10.1038/s41467-020-17314-1

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