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+)](i) in PASMCs. Collectively, we conclude that
hypoxia may induce Ca(2+) release by causing ROS-mediated dissociation of
FKBP12.6 from
RyR2 in PASMCs.