Open AccessImportant Role of Sarcoplasmic Reticulum Ca2+ReleaseviaRyanodine Receptor-2 Channel in Hypoxia-Induced Rieske Iron–Sulfur Protein-Mediated Mitochondrial Reactive Oxygen Species Generation in Pulmonary Artery Smooth Muscle Cells
Author(s) -
Zhao Yang,
Tengyao Song,
Lillian Truong,
Jorge ReyesGarcía,
Lan Wang,
YunMin Zheng,
Yong-Xiao Wang
Publication year - 2020
Publication title -
antioxidants and redox signaling
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 2.277
H-Index - 190
eISSN - 1557-7716
pISSN - 1523-0864
DOI - 10.1089/ars.2018.7652
Subject(s) - ryanodine receptor 2 , ryanodine receptor , mitochondrial ros , reactive oxygen species , hypoxic pulmonary vasoconstriction , endoplasmic reticulum , uniporter , microbiology and biotechnology , chemistry , hypoxia (environmental) , mitochondrion , caffeine , biology , biochemistry , endocrinology , oxygen , cytosol , vasoconstriction , organic chemistry , enzyme
Aims: It is known that mitochondrial reactive oxygen species generation ([ROS] m ) causes the release of Ca 2+ via ryanodine receptor-2 (RyR2) on the sarcoplasmic reticulum (SR) in pulmonary artery smooth muscle cells (PASMCs), playing an essential role in hypoxic pulmonary vasoconstriction (HPV). In this study, we sought to determine whether hypoxia-induced RyR2-mediated Ca 2+ release may in turn promote [ROS] m in PASMCs and the underlying signaling mechanism. Results: Our data reveal that application of caffeine or norepinephrine to induce Ca 2+ release increased [ROS] m in PASMCs. Likewise, exogenous Ca 2+ augmented ROS generation in isolated mitochondria and at complex III from PASMCs. Inhibition of mitochondrial Ca 2+ uniporter (MCU) with Ru360 attenuated agonist-induced [ROS] m . Ru360 produced a similar inhibitory effect on hypoxia-induced [ROS] m . Rieske iron-sulfur protein (RISP) gene knockdown inhibited Ca 2+ - and caffeine-induced [ROS] m . Inhibition of RyR2 by tetracaine or RyR2 gene knockout suppressed hypoxia-induced [ROS] m as well. Innovation: In this article, we present convincing evidence that Ca 2+ release following hypoxia or RyR simulation causes a significant increase in MCU, and the increased MCU subsequently RISP-dependent [ROS] m , which provides a positive feedback mechanism to enhance hypoxia-initiated [ROS] m in PASMCs. Conclusion: Our findings demonstrate that hypoxia-induced mitochondrial ROS-dependent SR RyR2-mediated Ca 2+ release increases MCU and then RISP-dependent [ROS] m in PASMCs, which may make significant contributions to HPV and associated pulmonary hypertension.