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

• Published in: Nature communications Vol. 11; no. 1; p. 3527
• Main Authors: 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
• Format: Journal Article
• Language: English
• Published: London Nature Publishing Group UK 15-07-2020; Nature Publishing Group; Nature Portfolio
• Subjects: 14/19; 42/89; 631/80/86/1999; 631/80/86/2372; 64/60; 692/699/1785; Animals; Calcium; Calcium ions; Calcium Signaling; Calcium signalling; Cell activation; Cell Proliferation; Channel gating; Cyclin D1; Cyclin D1 - metabolism; Cytosol - metabolism; Electron Transport Complex III - metabolism; Humanities and Social Sciences; Humans; Hypertension; Hypertension, Pulmonary - metabolism; Hypoxia; Hypoxia - pathology; Ion channels; Iron; Iron-sulfur proteins; Lung diseases; Male; Medical treatment; Mice; Mice, Inbred C57BL; Mice, Knockout; Mitochondria - metabolism; multidisciplinary; Muscles; Myocytes, Smooth Muscle - metabolism; NF-kappa B - metabolism; NF-κB protein; Oxygen - metabolism; Proteins; Pulmonary arteries; Pulmonary artery; Pulmonary Artery - pathology; Pulmonary hypertension; Reactive Oxygen Species - metabolism; Receptors; Respiration Disorders - metabolism; Rieske iron-sulfur protein; Ryanodine Receptor Calcium Release Channel - metabolism; Ryanodine receptors; Science; Science (multidisciplinary); Signal Transduction; Signaling; Smooth muscle; Stabilization; Sulfur; Tacrolimus; Tacrolimus Binding Proteins - metabolism; Tacrolimus-binding protein; Therapeutic applications
• ISSN: 2041-1723; 2041-1723
• DOI: 10.1038/s41467-020-17314-1

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.
Pulmonary hypertension is a devastating disease with elevation of pulmonary artery pressure and related to abnormal calcium signalling. Here, the authors show that suppression or stabilization of the calcium channel ryanodine receptor 2 may be a potential treatment approach for this disease.