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

AI Article Synopsis

  • Ca signaling in pulmonary arterial smooth muscle cells (PASMCs) is crucial for understanding pulmonary hypertension (PH), but the exact ion channel mechanisms are still unclear.
  • Research indicates that chronic hypoxia leads to increased ryanodine receptor (RyR) activity and decreased interaction with FKBP12.6, which affects calcium release in PASMCs.
  • Inhibiting specific proteins related to RyR2 activity can reduce cell proliferation and PH in mice, suggesting that stabilizing the RyR2/FKBP12.6 complex could be a potential treatment strategy for PH.

Article Abstract

Ca 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 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 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 release blockade may be potentially beneficial for the treatment of PH.

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Source
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7363799PMC
http://dx.doi.org/10.1038/s41467-020-17314-1DOI Listing

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