Hypoxia Induces Intracellular Ca²⁺ Release by Causing Reactive Oxygen Species-Mediated Dissociation of FK506-Binding Protein 12.6 from Ryanodine Receptor 2 in Pulmonary Artery Myocytes

Abstract

Here we attempted to test a novel hypothesis that hypoxia may induce Ca 2+ release through reactive oxygen species (ROS)-mediated dissociation of FK506-binding protein 12.6 (FKBP12.6) from ryanodine receptors (RyRs) on the sarcoplasmic reticulum (SR) in pulmonary artery smooth muscle cells (PASMCs). The results reveal that hypoxic exposure significantly decreased the amount of FKBP12.6 on the SR of PAs and increased FKBP12.6 in the cytosol. The colocalization of FKBP12.6 with RyRs was decreased in intact PASMCs. Pharmacological and genetic inhibition of intracellular ROS generation prevented hypoxia from decreasing FKBP12.6 on the SR and increasing FKBP12.6 in the cytosol. Exogenous ROS (H 2 O 2 ) reduced FKBP12.6 on the SR and augmented FKBP12.6 in the cytosol. Oxidized FKBP12.6 was absent on the SR from PAs pretreated with and without hypoxia, but it was present with a higher amount in the cytosol from PAs pretreated with than without hypoxia. Hypoxia and H 2 O 2 diminished the association of FKBP12.6 from type 2 RyRs (RyR2). The activity of RyRs was increased in PAs pretreated with hypoxia or H 2 O 2 . FKBP12.6 removal enhanced, whereas RyR2 gene deletion blocked the hypoxic increase in [Ca 2+

Mitochondrial Redox Signaling: Interaction of Mitochondrial Reactive Oxygen Species with Other Sources of Oxidative Stress

“…In a subsequent study they showed that hypoxia-triggered mtROS formation induces accumulation of cytoplasmic calcium (77). Meanwhile, Wang and coworkers have summarized their data on hypoxia-triggered mtROS with downstream Nox activation as well as effects of hypoxia-driven ROS formation on intracellular calcium levels in a comprehensive review (129).…”

Oxygen sensing and signal transduction in hypoxic pulmonary vasoconstriction

“…However, the hypothesis is limited by the fact that inhibition of L-type calcium channels or genetic deletion of K V channels only partially inhibited HPV [86,[143][144][145]. Moreover, ROS may trigger intracellular calcium release by interaction with sarcoplasmatic RyR receptors [146,147], but the contribution of intracellular calcium release could not be shown in all studies [49].…”

Protein kinase RNA-like endoplasmic reticulum kinase (PERK)/calcineurin signaling is a novel pathway regulating intracellular calcium accumulation which might be involved in ventricular arrhythmias in diabetic cardiomyopathy

“…Results from a recent study suggested that calcineurin is a down-stream molecule of PERK signaling by direct interaction with PERK [15]. Calcineurin is previously known to regulate ER calcium uptake and release by dissociating FK506-binding protein 12.6 (FKBP12.6) from RyR2-FKBP12 complex to regulate opening of this channel [16].…”