Role of FKBP12.6 in hypoxia- and norepinephrine-induced Ca2+ release and contraction in pulmonary artery myocytes

Zheng, Yun‐Min; Mei, Qibing; Wang, Qingsong; Abdullaev, Iskandar; Lai, F. Anthony; Xin, Hong‐Bo; Kotlikoff, Michael I.; Wang, Yong-Xiao

doi:10.1016/j.ceca.2003.09.006

Cited by 47 publications

(88 citation statements)

References 33 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

“…Oxidative stress, a condition where the production of reactive oxygen species overrides the scavenging effects of the antioxidant defense system and the associated intracellular Ca 2ϩ overload, has been implicated in the genesis of various cardiac diseases, including ischemia-reperfusion injury, diabetic and catecholamine-and doxorubicin-induced cardiomyopathies, and the transition from cardiac hypertrophy to heart failure (62)(63)(64). A role for FKBP12.6 has been proposed in hypoxia-induced, RyR2-mediated Ca 2ϩ signaling in vascular smooth muscle, since FKBP12.6 deficiency (gene knock-out or FK506 exposure) enhanced hypoxia-induced Ca 2ϩ release (65). Heart failure is a condition characterized by increased activity of the sympathetic nervous system and increased catecholamine levels.…”

Section: Controlmentioning

confidence: 99%

Redox Sensitivity of the Ryanodine Receptor Interaction with FK506-binding Protein

Zissimopoulos

Docrat

Lai

2007

Journal of Biological Chemistry

View full text Add to dashboard Cite

The ryanodine receptor (RyR) calcium release channel functions as a redox sensor that is sensitive to channel modulators. The FK506-binding protein (FKBP) is an important regulator of channel activity, and disruption of the RyR2-FKBP12.6 association has been implicated in cardiac disease. In the present study, we investigated whether the RyR-FKBP association is redoxregulated. Using co-immunoprecipitation assays of solubilized native RyR2 from cardiac muscle sarcoplasmic reticulum ( and diamide differentially affected the RyR2-FKBP12.6 interaction, decreasing binding to ϳ75 and ϳ50% of control, respectively. In addition, the effect of H 2 O 2 was negligible when the channel was in its closed state or when applied after FKBP binding had occurred, whereas diamide was always effective. A cysteine-null mutant FKBP12.6 retained redox-sensitive interaction with RyR2, suggesting that the effect of the redox reagents is exclusively via sites on the ryanodine receptor. K201 (or JTV519), a drug that has been proposed to prevent FKBP12.6 dissociation from the RyR2 channel complex, did not restore normal FKBP binding under oxidizing conditions. Our results indicate that the redox state of the RyR is intimately connected with FKBP binding affinity. Ryanodine receptors (RyRs)2 are tetrameric intracellular Ca 2ϩ channels that mediate the release of Ca 2ϩ from the sarco/ endoplasmic reticulum in muscle and nonmuscle cells (1). Three genes coding for mammalian RyRs have been identified: RyR1 in skeletal muscle, RyR2 in heart and brain, and RyR3 in a number of tissues. The deduced primary structure of all RyRs suggests a hydrophobic C terminus forming the channel pore, with the remaining ϳ80% being cytoplasmic. RyR channel activity is regulated by Ca 2ϩ , Mg 2ϩ , ATP, phosphorylation and redox status, and a number of accessory proteins.The immunophilin, FK506-binding protein (FKBP), a receptor protein for the immunosuppressants, FK506 and rapamycin, is an essential component of the RyR-Ca 2ϩ release channel complex in both skeletal and cardiac muscle (2, 3). RyR1 binds to both FKBP12 and FKBP12.6 with similar affinities (4), whereas RyR2 associates specifically with the FKBP12.6 isoform (3, 5). The stoichiometry of the association is four molecules of FKBP per RyR tetrameric channel (i.e. one FKBP molecule for each RyR protomer) (3, 6). Mapping studies have failed to identify a unique FKBP-binding site, with evidence presented for three distinct RyR regions (N-terminal, central, and C-terminal domains) (7-12), suggesting that FKBP interaction may be stabilized by multiple physical contacts and/or may be conformation-sensitive. The functional effects of FKBP association with RyR have been suggested to include stabilization of the full conductance state (7,13,14), channel closure (5, 6, 15), and coupled gating between neighboring channels (16,17). These effects are highlighted in abnormal or disease states, where defective regulation of the RyR-FKBP association has been implicated in cardiomyopathy (18), cardiac hypertrophy (19), h...

show abstract

Section: Controlmentioning

confidence: 99%

Redox Sensitivity of the Ryanodine Receptor Interaction with FK506-binding Protein

Zissimopoulos

Docrat

Lai

2007

Journal of Biological Chemistry

View full text Add to dashboard Cite

show abstract

“…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].…”

Section: Introductionmentioning

confidence: 99%

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

Self Cite

View full text Add to dashboard Cite

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...

show abstract

“…Many reports demonstrated that RyR-mediated Ca 2+ release (also called Ca 2+ spark) activates the BK Ca channel in plasmalemma, leads to VSM membrane hyperpolarization, and negatively regulates vascular tension [24] . Zheng et al reported that RyR-evoked Ca 2+ release is increased in hypoxic SMCs [10] , and our previous studies showed that over-activation of the BK Ca channel plays an important role in the occurrence of vascular hyporeactivity after hemorrhagic shock [12,13] , suggesting that RyR-mediated Ca 2+ release might be related to the development of vascular hyporeactivity after hemorrhagic shock. Because the stimulation of A 3 AR could inhibit RyRmediated Ca 2+ release from the ER, we then explored whether A 3 AR stimulation can reverse the decreased vascular hyporeactivity after hemorrhagic shock through a RyR-mediated Ca 2+ release and BK Ca channel dependent signal pathway.…”

Section: Discussionmentioning

confidence: 99%

“…RyR-mediated Ca 2+ release increases significantly [10] , which might contribute to the activation of the BK Ca channel. Our previous studies suggested that over-activation of the BK Ca channel is closely associated with vascular hyporeactivity after hemorrhagic shock in rats [11,12] , and stimulation of A 3 AR could inhibit RyR-mediated Ca 2+ release [13] .…”

Section: Acta Pharmacologica Sinica Npgmentioning

confidence: 99%

Stimulation of the adenosine A3 receptor reverses vascular hyporeactivity after hemorrhagic shock in rats

Zhou

Chen

et al. 2010

Acta Pharmacol Sin

View full text Add to dashboard Cite

Role of FKBP12.6 in hypoxia- and norepinephrine-induced Ca2+ release and contraction in pulmonary artery myocytes

Cited by 47 publications

References 33 publications

Redox Sensitivity of the Ryanodine Receptor Interaction with FK506-binding Protein

Redox Sensitivity of the Ryanodine Receptor Interaction with FK506-binding Protein

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

Stimulation of the adenosine A3 receptor reverses vascular hyporeactivity after hemorrhagic shock in rats

Contact Info

Product

Resources

About