scholarly journals Cardiac CaMKIIδ and Wenxin Keli Prevents Ang II-Induced Cardiomyocyte Hypertrophy by Modulating CnA-NFATc4 and Inflammatory Signaling Pathways in H9c2 Cells

2020 ◽  
Vol 2020 ◽  
pp. 1-17
Author(s):  
Na An ◽  
Yu Chen ◽  
Yanfen Xing ◽  
Honghua Wu ◽  
Xiongyi Gao ◽  
...  
Keyword(s):  
Signaling Pathways ◽  
Nuclear Translocation ◽  
Cardiomyocyte Hypertrophy ◽  
Ang Ii ◽  
H9c2 Cells ◽  
Patch Clamp Recording ◽  
Inflammatory Signaling ◽  
Calcium Calmodulin Dependent ◽  
Pathway Expression ◽  
Dependent Protein

Previous studies have demonstrated that calcium-/calmodulin-dependent protein kinase II (CaMKII) and calcineurin A-nuclear factor of activated T-cell (CnA-NFAT) signaling pathways play key roles in cardiac hypertrophy (CH). However, the interaction between CaMKII and CnA-NFAT signaling remains unclear. H9c2 cells were cultured and treated with angiotensin II (Ang II) with or without silenced CaMKIIδ (siCaMKII) and cyclosporine A (CsA, a calcineurin inhibitor) and subsequently treated with Wenxin Keli (WXKL). Patch clamp recording was conducted to assess L-type Ca2+ current (ICa-L), and the expression of proteins involved in signaling pathways was measured by western blotting. Myocardial cytoskeletal protein and nuclear translocation of target proteins were assessed by immunofluorescence. The results indicated that siCaMKII suppressed Ang II-induced CH, as evidenced by reduced cell surface area and ICa-L. Notably, siCaMKII inhibited Ang II-induced activation of CnA and NFATc4 nuclear transfer. Inflammatory signaling was inhibited by siCaMKII and WXKL. Interestingly, CsA inhibited CnA-NFAT pathway expression but activated CaMKII signaling. In conclusion, siCaMKII may improve CH, possibly by blocking CnA-NFAT and MyD88 signaling, and WXKL has a similar effect. These data suggest that inhibiting CaMKII, but not CnA, may be a promising approach to attenuate CH and arrhythmia progression.

scholarly journals The Yeast PH Domain Proteins Slm1 and Slm2 Are Targets of Sphingolipid Signaling during the Response to Heat Stress

2006 ◽  
Vol 27 (2) ◽  
pp. 633-650 ◽  
Author(s):  
Alexes Daquinag ◽  
Maria Fadri ◽  
Sung Yun Jung ◽  
Jun Qin ◽  
Jeannette Kunz
Keyword(s):  
Heat Stress ◽  
Signaling Pathways ◽  
Actin Polymerization ◽  
Mutational Analysis ◽  
Ph Domain ◽  
Calcium Calmodulin Dependent ◽  
Dependent Protein ◽  
A Site ◽  
Arginine Permease

ABSTRACT The PH domain-containing proteins Slm1 and Slm2 were previously identified as effectors of the phosphatidylinositol-4,5-bisphosphate (PI4,5P2) and TORC2 signaling pathways. Here, we demonstrate that Slm1 and Slm2 are also targets of sphingolipid signaling during the heat shock response. We show that upon depletion of cellular sphingolipid levels, Slm1 function becomes essential for survival under heat stress. We further demonstrate that Slm proteins are regulated by a phosphorylation/dephosphorylation cycle involving the sphingolipid-activated protein kinases Pkh1 and Pkh2 and the calcium/calmodulin-dependent protein phosphatase calcineurin. By using a combination of mass spectrometry and mutational analysis, we identified serine residue 659 in Slm1 as a site of phosphorylation. Characterization of Slm1 mutants that mimic dephosphorylated and phosphorylated states demonstrated that phosphorylation at serine 659 is vital for survival under heat stress and promotes the proper polarization of the actin cytoskeleton. Finally, we present evidence that Slm proteins are also required for the trafficking of the raft-associated arginine permease Can1 to the plasma membrane, a process that requires sphingolipid synthesis and actin polymerization. Together with previous work, our findings suggest that Slm proteins are subject to regulation by multiple signals, including PI4,5P2, TORC2, and sphingolipids, and may thus integrate inputs from different signaling pathways to temporally and spatially control actin polarization.

scholarly journals Calcineurin, a Calcium/Calmodulin-dependent Protein Phosphatase, Is Involved in Movement, Fertility, Egg Laying, and Growth inCaenorhabditis elegans

2002 ◽  
Vol 13 (9) ◽  
pp. 3281-3293 ◽  
Author(s):  
Jaya Bandyopadhyay ◽  
Jiyeon Lee ◽  
Jungsoo Lee ◽  
Jin Il Lee ◽  
Jae-Ran Yu ◽  
...  
Keyword(s):  
Signaling Pathways ◽  
Protein Phosphatase ◽  
Body Wall ◽  
Egg Laying ◽  
Α Subunit ◽  
C Elegans ◽  
Calcium Calmodulin Dependent ◽  
Dependent Protein ◽  
Identification And Characterization

Calcineurin is a Ca2+-calmodulin–dependent serine/threonine protein phosphatase that has been implicated in various signaling pathways. Here we report the identification and characterization of calcineurin genes in Caenorhabditis elegans (cna-1 and cnb-1), which share high homology with Drosophila and mammalian calcineurin genes. C. elegans calcineurin binds calcium and functions as a heterodimeric protein phosphatase establishing its biochemical conservation in the nematode. Calcineurin is expressed in hypodermal seam cells, body-wall muscle, vulva muscle, neuronal cells, and in sperm and the spermatheca. cnb-1 mutants showed pleiotropic defects including lethargic movement and delayed egg-laying. Interestingly, these characteristic defects resembled phenotypes observed in gain-of-function mutants ofunc-43/Ca2+-calmodulin–dependent protein kinase II (CaMKII) and goa-1/Go-protein α-subunit. Double mutants of cnb-1 andunc-43(gf) displayed an apparent synergistic severity of movement and egg-laying defects, suggesting that calcineurin may have an antagonistic role in CaMKII-regulated phosphorylation signaling pathways in C. elegans.

scholarly journals Dishevelled activates Ca2+ flux, PKC, and CamKII in vertebrate embryos

2003 ◽  
Vol 161 (4) ◽  
pp. 769-777 ◽  
Author(s):  
Laird C. Sheldahl ◽  
Diane C. Slusarski ◽  
Petra Pandur ◽  
Jeffrey R. Miller ◽  
Michael Kühl ◽  
...  
Keyword(s):  
Signaling Pathways ◽  
Heart Development ◽  
Intracellular Signaling ◽  
Planar Cell Polarity ◽  
Intracellular Protein ◽  
Dependent Protein Kinase ◽  
Calcium Calmodulin Dependent ◽  
Wnt Ligands ◽  
Dependent Protein ◽  
Vertebrate Embryos

Wnt ligands and Frizzled (Fz) receptors have been shown to activate multiple intracellular signaling pathways. Activation of the Wnt–β-catenin pathway has been described in greatest detail, but it has been reported that Wnts and Fzs also activate vertebrate planar cell polarity (PCP) and Wnt–Ca2+ pathways. Although the intracellular protein Dishevelled (Dsh) plays a dual role in both the Wnt–β-catenin and the PCP pathways, its potential involvement in the Wnt–Ca2+ pathway has not been investigated. Here we show that a Dsh deletion construct, XDshΔDIX, which is sufficient for activation of the PCP pathway, is also sufficient for activation of three effectors of the Wnt–Ca2+ pathway: Ca2+ flux, PKC, and calcium/calmodulin-dependent protein kinase II (CamKII). Furthermore, we find that interfering with endogenous Dsh function reduces the activation of PKC by Xfz7 and interferes with normal heart development. These data suggest that the Wnt–Ca2+ pathway utilizes Dsh, thereby implicating Dsh as a component of all reported Fz signaling pathways.

scholarly journals Adipose-Derived Extract Suppresses IL-1β-Induced Inflammatory Signaling Pathways in Human Chondrocytes and Ameliorates the Cartilage Destruction of Experimental Osteoarthritis in Rats

2021 ◽  
Vol 22 (18) ◽  
pp. 9781
Author(s):  
Hideki Ohashi ◽  
Keiichiro Nishida ◽  
Aki Yoshida ◽  
Yoshihisa Nasu ◽  
Ryuichi Nakahara ◽  
...  
Keyword(s):  
Signaling Pathways ◽  
Intracellular Signaling ◽  
Nuclear Translocation ◽  
Mapk Pathway ◽  
Cartilage Destruction ◽  
Mitogen Activated Protein Kinase ◽  
Human Chondrocytes ◽  
Inflammatory Signaling ◽  
Adipose Tissues ◽  
Experimental Osteoarthritis

We investigated the effects of adipose-derived extract (AE) on cultured chondrocytes and in vivo cartilage destruction. AE was prepared from human adipose tissues using a nonenzymatic approach. Cultured human chondrocytes were stimulated with interleukin-1 beta (IL-1β) with or without different concentrations of AE. The effects of co-treatment with AE on intracellular signaling pathways and their downstream gene and protein expressions were examined using real-time PCR, Western blotting, and immunofluorescence staining. Rat AE prepared from inguinal adipose tissues was intra-articularly delivered to the knee joints of rats with experimental osteoarthritis (OA), and the effect of AE on cartilage destruction was evaluated histologically. In vitro, co-treatment with IL-1β combined with AE reduced activation of the p38 and ERK mitogen-activated protein kinase (MAPK) pathway and nuclear translocation of the p65 subunit of nuclear factor-kappa B (NF-κB), and subsequently downregulated the expressions of matrix metalloproteinase (MMP)-1, MMP-3, MMP-13, a disintegrin and metalloproteinase with thrombospondin motifs (ADAMTS)-4, IL-6, and IL-8, whereas it markedly upregulated the expression of IL-1 receptor type 2 (IL-1R2) in chondrocytes. Intra-articular injection of homologous AE significantly ameliorated cartilage destruction six weeks postoperatively in the rat OA model. These results suggested that AE may exert a chondroprotective effect, at least in part, through modulation of the IL-1β-induced inflammatory signaling pathway by upregulation of IL-1R2 expression.

A role for T-type Ca2+channels in the synergistic control of aldosterone production by ANG II and K+

1999 ◽  
Vol 276 (5) ◽  
pp. F674-F683 ◽  
Author(s):  
Xiao-Liang Chen ◽  
Douglas A. Bayliss ◽  
Robert J. Fern ◽  
Paula Q. Barrett
Keyword(s):  
Reversal Potential ◽  
Ang Ii ◽  
Aldosterone Secretion ◽  
Calcium Calmodulin Dependent ◽  
Aldosterone Production ◽  
Control Production ◽  
Dependent Protein ◽  
Camkii Activation ◽  
Hyperpolarizing Shift ◽  
Ca2 Channels

Independently, plasma K+and ANG II stimulate aldosterone secretion from adrenal glomerulosa (AG) cells, but together they synergistically control production. We studied mechanisms to mediate this synergy using bovine AG cells studied under physiological conditions (in 1.25 mM Ca2+ at 37°C). Increasing K+ from 2 to 5 mM caused a potentiation of ANG II-induced aldosterone secretion and a substantial membrane depolarization (∼21 mV). ANG II inhibited a K+-selective conductance in both 2 and 5 mM K+ but caused only a slight depolarization because, under both conditions, membrane potential was close to the reversal potential of the ANG II-induced current. ANG II activated calcium/calmodulin-dependent protein kinase II (CaMKII) equivalently in 2 and 5 mM K+. However, CaMKII activation caused a hyperpolarizing shift in the activation of T-type Ca2+ channels, such that substantially more current was elicited at membrane potentials established by 5 mM K+. We propose that synergy in aldosterone secretion results from K+-induced depolarization and ANG II-induced modulation of T-type channel activation, such that together they promote enhanced steady-state Ca2+ flux.

scholarly journals CYP2J2-Derived EETs Attenuated Angiotensin II-Induced Adventitial Remodeling via Reduced Inflammatory Response

2016 ◽  
Vol 39 (2) ◽  
pp. 721-739 ◽  
Author(s):  
Chi Zhou ◽  
Jin Huang ◽  
Junxiong Chen ◽  
Jinsheng Lai ◽  
Fasheng Zhu ◽  
...  
Keyword(s):  
Angiotensin Ii ◽  
Gene Delivery ◽  
Signaling Pathways ◽  
Nuclear Translocation ◽  
Wall Thickening ◽  
Protective Effects ◽  
Ang Ii ◽  
Independent Manner ◽  
Stat3 Phosphorylation ◽  
Arachidonic Acids

Background: Cytochrome P450 (CYP) epoxygenases metabolize arachidonic acids (AA) to form epoxyeicosatrienoic acids (EETs), which exert beneficial roles in the treatment of cardiovascular diseases, but little is known about its role on adventitial remodeling. Methods: We used C57BL/6J mice in vivo and primary rat adventitial fibroblasts (AFs) in vitro treated with Angiotensin II to investigate the effects of CYP2J2 gene delivery and exogenous EETs administration on adventitial remodeling. Results: CYP/sEH system was found to exist in human adventitia, and involved in adventitial remodeling process. Exogenous EETs administration significantly inhibited Ang II-induced AFs activation, characterized by differentiation, proliferation, migration, and collagen synthesis. These protective effects were partially reversed by PPARγ antagonist GW9662 pretreatment or SOCS3 siRNA transfection. EETs suppressed Ang II-induced IκBα phosphorylation, subsequent NF-κB nuclear translocation via PPARγ dependent signaling pathway in AFs. Additionally, EETs reduced Ang II-induced JAK2, STAT3 phosphorylation and subsequent phosphor-STAT3 nuclear translocation, which were mediated by SOCS3 induction but independent of PPARγ activation. Furthermore, rAAV-CYP2J2 gene delivery reduced vessel wall thickening, AFs differentiation, proliferation and collagen deposition in aortic adventitia induced by Ang II infusion, which were mediated by NF-κB and SOCS3/JAK/STAT signaling pathways in blood pressure dependent and independent manner, respectively. Conclusion: We concluded that CYP2J2 overexpression attenuated Ang II-induced adventitial remodeling via PPARγ-dependent NF-κB and PPARγ-independent SOCS3/JAK/STAT inflammatory signaling pathways.

scholarly journals CaMKII Serine 280 O-GlcNAcylation Links Diabetic Hyperglycemia to Proarrhythmia

2021 ◽  
Author(s):  
Bence Hegyi ◽  
Anna Fasoli ◽  
Christopher Y Ko ◽  
Benjamin W Van ◽  
Chidera C Alim ◽  
...  
Keyword(s):  
Angiotensin Ii ◽  
Ang Ii ◽  
Post Translational Modifications ◽  
Acute Hyperglycemia ◽  
Calcium Calmodulin Dependent ◽  
Patients With Diabetes ◽  
Normal Glucose ◽  
Dependent Protein ◽  
Delayed Afterdepolarizations

Rationale: Diabetic hyperglycemia is associated with cardiac dysfunction and increased arrhythmia risk, and calcium/calmodulin-dependent protein kinase II (CaMKII) function has been implicated. CaMKII activity is promoted by both oxidation and O linked β-N-acetylglucosamine (O GlcNAc) of known CaMKII sites. Objective: To investigate which post-translational modifications occur in human diabetic hearts and how they alter electrophysiological and Ca 2+ handling properties in hyperglycemia. Methods and Results: We assessed echocardiography, electrophysiology, Ca 2+ -handling, and protein expression in site-specific CaMKII mutant mice (O GlcNAc-resistant S280A and oxidation-resistant MM281/2VV knock-ins, and global and cardiac-specific knockouts), in myocytes subjected to acute hyperglycemia and angiotensin II (Ang-II) and mice after streptozotocin injections (to induce diabetes). Human patients with diabetes exhibit elevated CaMKII O GlcNAcylation but not oxidation. In mice, acute hyperglycemia increased spontaneous diastolic Ca 2+ sparks and waves and arrhythmogenic action potential changes (prolongation, alternans and delayed afterdepolarizations), all of which required CaMKII-S280 O GlcNAcylation. Ang-II effects were dependent on NADPH oxidase 2 (NOX2)-mediated CaMKII MM281/2 oxidation. Diabetes led to much greater Ca 2+ leak, RyR2 S2814 phosphorylation, electrophysiological remodeling, and increased susceptibility to in vivo arrhythmias, requiring CaMKII activation, predominantly via S280 O GlcNAcylation and less via MM281/2 oxidation. These effects were present in myocytes at normal glucose, but were exacerbated with the in-vivo high circulating glucose. Phospholamban (PLB) O-GlcNAcylation was increased and coincided with reduced PLB S16 phosphorylation in diabetes. Dantrolene, that reverses CaMKII-dependent proarrhythmic RyR-mediated Ca 2+ leak, also prevented hyperglycemia-induced APD prolongation and delayed afterdepolarizations. Conclusions: We found that CaMKII-S280 O GlcNAcylation is required for increased arrhythmia susceptibility in diabetic hyperglycemia, which can be worsened by an additional angiotensin II-NOX2-CaMKII MM281/2 oxidation pathway. CaMKII-dependent RyR2 S2814 phosphorylation markedly increases proarrhythmic Ca 2+ leak and PLB O-GlcNAcylation may limit SR Ca 2+ reuptake, leading to impaired excitation-contraction coupling and arrhythmogenesis in diabetic hyperglycemia.

scholarly journals p38 Mitogen-activated Protein Kinase-, Calcium-Calmodulin–dependent Protein Kinase-, and Calcineurin-mediated Signaling Pathways Transcriptionally Regulate Myogenin Expression

2002 ◽  
Vol 13 (6) ◽  
pp. 1940-1952 ◽  
Author(s):  
Qing Xu ◽  
Lu Yu ◽  
Lanying Liu ◽  
Ching Fung Cheung ◽  
Xue Li ◽  
...  
Keyword(s):  
Protein Kinase ◽  
Signaling Pathways ◽  
Histone Deacetylases ◽  
Mitogen Activated Protein Kinase ◽  
Cis Elements ◽  
Dependent Protein Kinase ◽  
Calcium Calmodulin Dependent ◽  
Mitogen Activated Protein ◽  
Rd Cells ◽  
Dependent Protein

In this report, we identify myogenin as an important transcriptional target under the control of three intracellular signaling pathways, namely, the p38 mitogen-activated protein kinase- (MAPK), calcium-calmodulin–dependent protein kinase- (CaMK), and calcineurin-mediated pathways, during skeletal muscle differentiation. Three cis-elements (i.e., the E box, myocyte enhancer factor [MEF] 2, and MEF3 sites) in the proximal myogenin promoter in response to these three pathways are defined. MyoD, MEF2s, and Six proteins, the trans-activators bound to these cis-elements, are shown to be activated by these signaling pathways. Our data support a model in which all three signaling pathways act in parallel but nonredundantly to control myogenin expression. Inhibition of any one pathway will result in abolished or reduced myogenin expression and subsequent phenotypic differentiation. In addition, we demonstrate that CaMK and calcineurin fail to activate MEF2s in Rhabdomyosarcoma-derived RD cells. For CaMK, we show its activation in response to differentiation signals and its effect on the cytoplasmic translocation of histone deacetylases 5 are not compromised in RD cells, suggesting histone deacetylases 5 cytoplasmic translocation is necessary but not sufficient, and additional signal is required in conjunction with CaMK to activate MEF2 proteins.

scholarly journals HOTAIR Up-Regulation Activates NF-κB to Induce Immunoescape in Gliomas

2021 ◽  
Vol 12 ◽  
Author(s):  
Yunfei Wang ◽  
Kaikai Yi ◽  
Xing Liu ◽  
Yanli Tan ◽  
Weili Jin ◽  
...  
Keyword(s):  
T Cell ◽  
Signaling Pathways ◽  
Rna Polymerase Ii ◽  
Transcription Initiation ◽  
Tumor Metastasis ◽  
Nuclear Translocation ◽  
Immune Escape ◽  
Glioma Cells ◽  
Inflammatory Signaling ◽  
Iκb Kinase

BackgroundCheckpoint blockade therapies targeting programmed death ligand 1 (PD-L1) and its receptor programmed cell death 1 promote T cell-mediated immune surveillance against tumors and have been associated with significant clinical benefit in cancer patients. The long-stranded non-coding RNA HOTAIR is highly expressed and associated with metastasis in a variety of cancer types and promotes tumor metastasis at least in part through association with the PRC2 complex that induces redirection to hundreds of genes involved in tumor metastasis. Here, we report that HOTAIR is an activator lncRNA of the NF-κB pathway and demonstrate that its apparent upregulation promotes inflammatory signaling and immune escape in glioma cells.MethodsBioinformatics analysis was used to elucidate the relationship between HOTAIR and NF-κB pathway in HOTAIR knockdown glioma cells. At the cytological level, protein hybridization and immunofluorescence were used to detect the response of proteins in the NF-κB signaling pathway to HOTAIR regulation. ChIP and ChIRP experiments identified HOTAIR target genes. Animal experiments verified alterations in inflammation and immune escape following HOTAIR knockdown and activity inhibition.ResultsHOTAIR activated the expression of proteins involved in NF-κB, TNFα, MAPK and other inflammatory signaling pathways. In addition, HOTAIR induced various proteins containing protein kinase structural domains and promoted the enrichment of proteins and complexes of important inflammatory signaling pathways, such as the TNFα/NF-κB signaling protein complex, the IκB kinase complex, and the IKKA-IKKB complex. In addition, HOTAIR aberrantly activated biological processes involved in glioma immune responses, T-cell co-stimulation and transcription initiation by RNA polymerase II. HOTAIR facilitated the induction of IκBα phosphorylation by suppressing the expression of the NF-κB upstream protein UBXN1, promoting NF-κB phosphorylation and nuclear translocation. In vivo, reduction of HOTAIR decreased PD-L1 protein expression, indicating that cells are more likely to be targeted by immune T cells.ConclusionIn conclusion, our results provide convincing evidence that lncRNA HOTAIR drives aberrant gene transcription and immune escape from tumor cells through the NF-κB pathway.

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