Rieske iron-sulfur protein induces FKBP12.6/RyR2 complex remodeling and subsequent pulmonary hypertension through NF-\u03baB/cyclin D1 pathway

Lin Mei,Leroy C Joseph,Vishal R Yadav,Lillian Truong,Hiroshi Takeshima,Yong-Xiao Wang,Marc A Judson,Sharath Kandhi,Yun-Min Zheng,Tengyao Song,Margarida M Barroso

doi:10.1038/s41467-020-17314-1

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.

Highlights

Ca2+ signaling in pulmonary arterial smooth muscle cells (PASMCs) plays an important role in pulmonary hypertension (PH)
Our current study has identified that RyR2 plays an important role in mediating PH
A series of our previous invitro studies further indicate that all three ryanodine receptor (RyR) subtypes are involved in hypoxia-induced Ca2+ and contractile responses in PASMCs, but RyR2 is a very important player[7,8,9]

Summary

Introduction

Ca2+ signaling in pulmonary arterial smooth muscle cells (PASMCs) plays an important role in pulmonary hypertension (PH). Pulmonary hypertension (PH) is a common disease with a short median survival time after diagnosis mostly because of limited specific and effective therapeutic options[1] This devastating condition often occurs in respiratory illnesses (e.g., chronic obstructive pulmonary disease) and high-altitude residence due primarily to chronic hypoxia (CH)-induced pulmonary artery (PA) constriction and remodeling. We have shown that RyR2-mediated Ca2+ release serves as an instrumental process in hypoxia-evoked contraction and remodeling[7,8,9], which are linked to canonical transient receptor potential (TRPC) channel activation and voltagedependent K+ (Kv) channel inhibition[10] These data suggest that RyRs are integral to the development of hypoxic cellular responses in PASMCs. whether and how RyR2mediated Ca2+ signaling exerts its role in the development of PH and the underlying molecular mechanisms are unknown.

Methods

Results

Conclusion