Type-3 Ryanodine Receptors Mediate Hypoxia-, but Not Neurotransmitter-induced Calcium Release and Contraction in Pulmonary Artery Smooth Muscle Cells

Zheng, Yun‐Min; Wang, Qingsong; Rathore, Rakesh; Zhang, Wanhui; Mazurkiewicz, Joseph E.; Sorrentino, Vincenzo; Singer, Harold A.; Kotlikoff, Michael I.; Wang, Yong-Xiao

doi:10.1085/jgp.200409232

Cited by 81 publications

(136 citation statements)

References 68 publications

(141 reference statements)

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“…Although there are many reports to suggest a pre-eminent role for inhibition of K + channels by hypoxia, with subsequent membrane depolarization and Ca 2+ entry via voltage-dependent Ca 2+ channels [1], others have provided evidence for capacitative Ca 2+ entry through store-operated channels [8; 29]. Intracellular Ca 2+ release is also a critical event for the elevation of [Ca 2+ ] i and constriction in PASMCs [2][3][4][5][6][7]. PKC and other protein kinases are implicated in hypoxic responses [30].…”

Section: Discussionmentioning

confidence: 99%

“…Freshly isolated mouse resistance pulmonary and mesenteric artery SMCs (PASMCs and MASMCs) and tissues were prepared as described previously [7]. Briefly, mice were euthanized by sodium pentobarbital (150 mg/kg, i.p.).…”

Section: Cell and Tissue Preparationmentioning

confidence: 99%

“…[Ca 2+ ] i were measured by a dual excitation wavelength fluorescence method using the IonOptix fluorescence photometric system (Milton, MA), as described previously [7]. Freshly isolated cells were loaded with 5 μM fura-2/AM.…”

Section: Measurement Of [Ca 2+ ] Imentioning

confidence: 99%

“…Fura-2/AM, and 5,6-chloromethyl-2,7-dichlorodihydrofluorescein diacetate (CM-DCF-DA) were obtained from Molecular Probes (Eugene, OR); PKCɛ translocation peptide inhibitor from Calbiochem (La Jolla, CA); monoclonal antibodies to PKCɛ, PKC inhibitor, Protein Gcoated beads from Santa Cruz (Santa Cruz, CA); and rotenone, myxothiazol, hydrogen peroxide, phorbol 12-myristate 13-acetate (PMA), GÖ6976, myeline basic protein (4)(5)(6)(7)(8)(9)(10)(11)(12)(13)(14), phosphatidyl serine, diolein, histone IIIs from Sigma (St. Louis, MO).…”

Section: Reagentsmentioning

confidence: 99%

“…In contrast, SMCs from systemic arteries display decreased [Ca 2+ ] i and relax in response to hypoxia. The response of PASMCs to acute hypoxia involves calcium entry through voltagedependent and store-operated Ca 2+ channels, as well as Ca 2+ release from the sarcoplasmic reticulum [1][2][3][4][5][6][7][8]. Hypoxia-dependent changes in reactive oxygen species (ROS) concentration have been proposed to mediate HPV by several laboratories, although the details of this hypothesis differ greatly [9; 10].…”

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Mitochondrial ROS-PKCε signaling axis is uniquely involved in hypoxic increase in [Ca2+]i in pulmonary artery smooth muscle cells

Rathore

Zheng

et al. 2006

Biochemical and Biophysical Research Communications

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The molecular mechanisms underlying hypoxic responses in pulmonary and systemic arteries remain obscure. Here we for the first time report that acute hypoxia significantly increased total PKC and PKCɛ activity in pulmonary, but not mesenteric arteries, while these two tissues showed comparable PKCɛ protein expression and activation by the PKC activator phorbol 12-myristate 13-acetate. Hypoxia induced an increase in intracellular reactive oxygen species (ROS) generation in isolated pulmonary artery smooth muscle cells (PASMCs), but not in mesenteric artery SMCs. Inhibition of mitochondrial ROS generation with rotenone, myxothiazol, or glutathione peroxidase-1 overexpression, prevented hypoxia-induced increases in total PKC and PKCɛ activity in pulmonary arteries. The inhibitory effects of rotenone were reversed by exogenous hydrogen peroxide. A PKCɛ translocation peptide inhibitor or PKCɛ gene deletion decreased hypoxic increase in [Ca 2+ ] i in PASMCs, whereas the conventional PKC inhibitor GÖ6976 had no effect. These data suggest that acute hypoxia may specifically increase mitochondrial ROS generation, which subsequently activates PKC, particularly PKCɛ, contributing to hypoxia-induced increase in [Ca 2+ ] i and contraction in PASMCs. KeywordsHypoxia; protein kinase C; reactive oxygen species; mitochondria; intracellular calcium; pulmonary artery smooth muscle cells Hypoxic pulmonary vasoconstriction (HPV) is observed in isolated lungs, pulmonary arteries, and pulmonary artery smooth muscle cells (PASMCs). The pulmonary circulation differs from the systemic circulation in response to oxygen tension; pulmonary arteries constrict to physiological hypoxia (~ 20-60 mmHg PO 2 ), whereas systemic arteries vasodilate. The mechanisms for these opposing responses to hypoxia appear to lie within the vascular SMCs. Hypoxia increases intracellular Ca 2+ concentration ([Ca 2+ ] i ) and contracts PASMCs. In contrast, SMCs from systemic arteries display decreased [Ca 2+ ] i and relax in response to hypoxia. The response of PASMCs to acute hypoxia involves calcium entry through voltagedependent and store-operated Ca 2+ channels, as well as Ca 2+ release from the sarcoplasmic reticulum [1][2][3][4][5][6][7][8]. Hypoxia-dependent changes in reactive oxygen species (ROS) concentration have been proposed to mediate HPV by several laboratories, although the details of this hypothesis differ greatly [9; 10]. However, the signaling pathways underlying artery-specific, acute hypoxic vasoconstriction remain to be fully elucidated. AnimalsPKCɛ −/− mice were purchased from the Jackson Laboratory (Bar Harbor, ME); Swiss-Webster mice from Taconic (Germantown, NY). Glutathione peroxidase-1 (Gpx1) overexpression mice were generated and maintained as described previously [18]. All animal experiments were approved by the Institutional Animal Care and Use Committee of Albany Medical College. To examine the effects of pharmacological reagents, control experiments were carried out in cells or tissues from the same mice. For experimen...

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Section: Discussionmentioning

confidence: 99%

Section: Cell and Tissue Preparationmentioning

confidence: 99%

Section: Measurement Of [Ca 2+ ] Imentioning

confidence: 99%

Section: Reagentsmentioning

confidence: 99%

mentioning

confidence: 99%

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Mitochondrial ROS-PKCε signaling axis is uniquely involved in hypoxic increase in [Ca2+]i in pulmonary artery smooth muscle cells

Rathore

Zheng

et al. 2006

Biochemical and Biophysical Research Communications

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Roles of different mitochondrial electron transport chain complexes in hypoxia‐induced pulmonary vasoconstriction

Yang

Zhuan

Yan

et al. 2015

Cell Biology International

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This study was designed to investigate the roles of different mitochondrial electron transport chain (ETC) complexes (I, II, III, and IV) on hypoxia-induced hypoxic pulmonary vasoconstriction (HPV). The third and fourth pulmonary arteries were collected from the normal tissues adjacent to tumors in 16 patients with lung cancer who had undergone lung cancer resections to isolate pulmonary artery smooth muscle cells (PASMCs). PASMCs were divided into seven groups and exposed to one of the following treatments: (1) normoxia (21% O(2), 5% CO(2), and 74% N(2)); (2) hypoxia (1% O(2), 5% CO(2), 94% N(2)); (3) hypoxia plus ETC complex I inhibitor MPP; (4) hypoxia plus ETC complex II inhibitor TTFA; (5) hypoxia plus ETC complex III Q(o) (pre) site inhibitor myxothiazol; (6) hypoxia plus ETC complex III Qi (post) site inhibitor antimycin A; (7) hypoxia plus ETC complex IV inhibitor NaN(3). Intracellular [Ca(2+) ]i and [ROS]i, mitochondrial [ROS]i, and PA rings tension were measured. Intracellular [Ca(2+) ]i and [ROS]i, mitochondrial [ROS]i, and PA ring tension were increased after hypoxia for 10 min. Mitochondrial ETC complex inhibitor MPP, TTFA, and myxothiazol significantly reduced [Ca(2+) ]i [ROS]i and PA tension (P < 0.01), whereas antimycin A and NaN(3) did not effectively reduce them. These results demonstrated it were mitochondrial ETC complex I, II, and III Q(o) site but not III Q(i) site and complex IV contribute to hypoxic pulmonary vasoconstriction and pulmonary hypertension.

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Hypoxic Pulmonary Hypertension of the Newborn

Gao

Raj

2010

Comprehensive Physiology

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Hypoxic pulmonary hypertension of the newborn is characterized by elevated pulmonary vascular resistance and pressure due to vascular remodeling and increased vessel tension secondary to chronic hypoxia during the fetal and newborn period. In comparison to the adult, the pulmonary vasculature of the fetus and the newborn undergoes tremendous developmental changes that increase susceptibility to a hypoxic insult. Substantial evidence indicates that chronic hypoxia alters the production and responsiveness of various vasoactive agents such as endothelium-derived nitric oxide, endothelin-1, prostanoids, platelet-activating factor, and reactive oxygen species, resulting in sustained vasoconstriction and vascular remodeling. These changes occur in most cell types within the vascular wall, particularly endothelial and smooth muscle cells. At the cellular level, suppressed nitric oxide-cGMP signaling and augmented RhoA-Rho kinase signaling appear to be critical to the development of hypoxic pulmonary hypertension of the newborn.

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Type-3 Ryanodine Receptors Mediate Hypoxia-, but Not Neurotransmitter-induced Calcium Release and Contraction in Pulmonary Artery Smooth Muscle Cells

Cited by 81 publications

References 68 publications

Mitochondrial ROS-PKCε signaling axis is uniquely involved in hypoxic increase in [Ca2+]i in pulmonary artery smooth muscle cells

Mitochondrial ROS-PKCε signaling axis is uniquely involved in hypoxic increase in [Ca2+]i in pulmonary artery smooth muscle cells

Roles of different mitochondrial electron transport chain complexes in hypoxia‐induced pulmonary vasoconstriction

Hypoxic Pulmonary Hypertension of the Newborn

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