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Macrophage Apoptosis and Efferocytosis in the Pathogenesis of Atherosclerosis.
Linton MF, Babaev VR, Huang J, Linton EF, Tao H, Yancey PG
(2016) Circ J 80: 2259-2268
MeSH Terms: Animals, Atherosclerosis, Endoplasmic Reticulum Stress, Humans, I-kappa B Kinase, Isoenzymes, Macrophages, Mechanistic Target of Rapamycin Complex 2, Mitogen-Activated Protein Kinase 8, Multiprotein Complexes, Proto-Oncogene Proteins c-akt, Signal Transduction, TOR Serine-Threonine Kinases, Unfolded Protein Response
Show Abstract · Added April 10, 2018
Macrophage apoptosis and the ability of macrophages to clean up dead cells, a process called efferocytosis, are crucial determinants of atherosclerosis lesion progression and plaque stability. Environmental stressors initiate endoplasmic reticulum (ER) stress and activate the unfolded protein response (UPR). Unresolved ER stress with activation of the UPR initiates apoptosis. Macrophages are resistant to apoptotic stimuli, because of activity of the PI3K/Akt pathway. Macrophages express 3 Akt isoforms, Akt1, Akt2 and Akt3, which are products of distinct but homologous genes. Akt displays isoform-specific effects on atherogenesis, which vary with different vascular cell types. Loss of macrophage Akt2 promotes the anti-inflammatory M2 phenotype and reduces atherosclerosis. However, Akt isoforms are redundant with regard to apoptosis. c-Jun NH-terminal kinase (JNK) is a pro-apoptotic effector of the UPR, and the JNK1 isoform opposes anti-apoptotic Akt signaling. Loss of JNK1 in hematopoietic cells protects macrophages from apoptosis and accelerates early atherosclerosis. IκB kinase α (IKKα, a member of the serine/threonine protein kinase family) plays an important role in mTORC2-mediated Akt signaling in macrophages, and IKKα deficiency reduces macrophage survival and suppresses early atherosclerosis. Efferocytosis involves the interaction of receptors, bridging molecules, and apoptotic cell ligands. Scavenger receptor class B type I is a critical mediator of macrophage efferocytosis via the Src/PI3K/Rac1 pathway in atherosclerosis. Agonists that resolve inflammation offer promising therapeutic potential to promote efferocytosis and prevent atherosclerotic clinical events. (Circ J 2016; 80: 2259-2268).
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Jnk1 Deficiency in Hematopoietic Cells Suppresses Macrophage Apoptosis and Increases Atherosclerosis in Low-Density Lipoprotein Receptor Null Mice.
Babaev VR, Yeung M, Erbay E, Ding L, Zhang Y, May JM, Fazio S, Hotamisligil GS, Linton MF
(2016) Arterioscler Thromb Vasc Biol 36: 1122-31
MeSH Terms: Animals, Aorta, Aortic Diseases, Apoptosis, Atherosclerosis, Bone Marrow Cells, Bone Marrow Transplantation, Cell Survival, Cells, Cultured, Diet, High-Fat, Disease Models, Animal, Endoplasmic Reticulum Stress, Genetic Predisposition to Disease, Hypercholesterolemia, Macrophages, Mice, Inbred C57BL, Mice, Knockout, Mitogen-Activated Protein Kinase 8, Mitogen-Activated Protein Kinase 9, PTEN Phosphohydrolase, Phenotype, Plaque, Atherosclerotic, Protein Kinase Inhibitors, Proto-Oncogene Proteins c-akt, Receptors, LDL, Signal Transduction, bcl-Associated Death Protein
Show Abstract · Added April 10, 2018
OBJECTIVE - The c-Jun NH2-terminal kinases (JNK) are regulated by a wide variety of cellular stresses and have been implicated in apoptotic signaling. Macrophages express 2 JNK isoforms, JNK1 and JNK2, which may have different effects on cell survival and atherosclerosis.
APPROACH AND RESULTS - To dissect the effect of macrophage JNK1 and JNK2 on early atherosclerosis, Ldlr(-/-) mice were reconstituted with wild-type, Jnk1(-/-), and Jnk2(-/-) hematopoietic cells and fed a high cholesterol diet. Jnk1(-/-)→Ldlr(-/-) mice have larger atherosclerotic lesions with more macrophages and fewer apoptotic cells than mice transplanted with wild-type or Jnk2(-/-) cells. Moreover, genetic ablation of JNK to a single allele (Jnk1(+/-)/Jnk2(-/-) or Jnk1(-/-)/Jnk2(+/-)) in marrow of Ldlr(-/-) recipients further increased atherosclerosis compared with Jnk1(-/-)→Ldlr(-/-) and wild-type→Ldlr(-/-) mice. In mouse macrophages, anisomycin-mediated JNK signaling antagonized Akt activity, and loss of Jnk1 gene obliterated this effect. Similarly, pharmacological inhibition of JNK1, but not JNK2, markedly reduced the antagonizing effect of JNK on Akt activity. Prolonged JNK signaling in the setting of endoplasmic reticulum stress gradually extinguished Akt and Bad activity in wild-type cells with markedly less effects in Jnk1(-/-) macrophages, which were also more resistant to apoptosis. Consequently, anisomycin increased and JNK1 inhibitors suppressed endoplasmic reticulum stress-mediated apoptosis in macrophages. We also found that genetic and pharmacological inhibition of phosphatase and tensin homolog abolished the JNK-mediated effects on Akt activity, indicating that phosphatase and tensin homolog mediates crosstalk between these pathways.
CONCLUSIONS - Loss of Jnk1, but not Jnk2, in macrophages protects them from apoptosis, increasing cell survival, and this accelerates early atherosclerosis.
© 2016 American Heart Association, Inc.
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Arrestin-3 binds c-Jun N-terminal kinase 1 (JNK1) and JNK2 and facilitates the activation of these ubiquitous JNK isoforms in cells via scaffolding.
Kook S, Zhan X, Kaoud TS, Dalby KN, Gurevich VV, Gurevich EV
(2013) J Biol Chem 288: 37332-42
MeSH Terms: Animals, Arrestins, COS Cells, Cell Proliferation, Cell Survival, Chlorocebus aethiops, Enzyme Activation, Isoenzymes, MAP Kinase Kinase 7, MAP Kinase Kinase Kinase 5, MAP Kinase Signaling System, Mice, Mice, Knockout, Mitogen-Activated Protein Kinase 8, Mitogen-Activated Protein Kinase 9, Phosphorylation, Protein Binding
Show Abstract · Added February 12, 2015
Non-visual arrestins scaffold mitogen-activated protein kinase (MAPK) cascades. The c-Jun N-terminal kinases (JNKs) are members of MAPK family. Arrestin-3 has been shown to enhance the activation of JNK3, which is expressed mainly in neurons, heart, and testes, in contrast to ubiquitous JNK1 and JNK2. Although all JNKs are activated by MKK4 and MKK7, both of which bind arrestin-3, the ability of arrestin-3 to facilitate the activation of JNK1 and JNK2 has never been reported. Using purified proteins we found that arrestin-3 directly binds JNK1α1 and JNK2α2, interacting with the latter comparably to JNK3α2. Phosphorylation of purified JNK1α1 and JNK2α2 by MKK4 or MKK7 is increased by arrestin-3. Endogenous arrestin-3 interacted with endogenous JNK1/2 in different cell types. Arrestin-3 also enhanced phosphorylation of endogenous JNK1/2 in intact cells upon expression of upstream kinases ASK1, MKK4, or MKK7. We observed a biphasic effect of arrestin-3 concentrations on phosphorylation of JNK1α1 and JNK2α2 both in vitro and in vivo. Thus, arrestin-3 acts as a scaffold, facilitating JNK1α1 and JNK2α2 phosphorylation by MKK4 and MKK7 via bringing JNKs and their activators together. The data suggest that arrestin-3 modulates the activity of ubiquitous JNK1 and JNK2 in non-neuronal cells, impacting the signaling pathway that regulates their proliferation and survival.
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Cannabinoid receptor 1 suppresses transient receptor potential vanilloid 1-induced inflammatory responses to corneal injury.
Yang Y, Yang H, Wang Z, Varadaraj K, Kumari SS, Mergler S, Okada Y, Saika S, Kingsley PJ, Marnett LJ, Reinach PS
(2013) Cell Signal 25: 501-11
MeSH Terms: Animals, Arachidonic Acids, Benzoxazines, Calcium, Calcium Channel Blockers, Cell Line, Disease Models, Animal, Endocannabinoids, Epithelial Cells, Epithelium, Corneal, Glycerides, Humans, Immunity, Innate, MAP Kinase Kinase Kinases, Mice, Mice, Knockout, Mitogen-Activated Protein Kinase 8, Morpholines, Naphthalenes, Patch-Clamp Techniques, Pertussis Toxin, Protein Binding, RNA Interference, RNA, Small Interfering, Receptor, Cannabinoid, CB1, Signal Transduction, TRPV Cation Channels, Wound Healing
Show Abstract · Added June 1, 2014
Cannabinoid receptor type 1 (CB1)-induced suppression of transient receptor potential vanilloid type 1 (TRPV1) activation provides a therapeutic option to reduce inflammation and pain in different animal disease models through mechanisms involving dampening of TRPV1 activation and signaling events. As we found in both mouse corneal epithelium and human corneal epithelial cells (HCEC) that there is CB1 and TRPV1 expression colocalization based on overlap of coimmunostaining, we determined in mouse corneal wound healing models and in human corneal epithelial cells (HCEC) if they interact with one another to reduce TRPV1-induced inflammatory and scarring responses. Corneal epithelial debridement elicited in vivo a more rapid wound healing response in wildtype (WT) than in CB1(-/-) mice suggesting functional interaction between CB1 and TRPV1. CB1 activation by injury is tenable based on the identification in mouse corneas of 2-arachidonylglycerol (2-AG) with tandem LC-MS/MS, a selective endocannabinoid CB1 ligand. Suppression of corneal TRPV1 activation by CB1 is indicated since following alkali burning, CB1 activation with WIN55,212-2 (WIN) reduced immune cell stromal infiltration and scarring. Western blot analysis of coimmunoprecipitates identified protein-protein interaction between CB1 and TRPV1. Other immunocomplexes were also identified containing transforming growth factor kinase 1 (TAK1), TRPV1 and CB1. CB1 siRNA gene silencing prevented suppression by WIN of TRPV1-induced TAK1-JNK1 signaling. WIN reduced TRPV1-induced Ca(2+) transients in fura2-loaded HCEC whereas pertussis toxin (PTX) preincubation obviated suppression by WIN of such rises caused by capsaicin (CAP). Whole cell patch clamp analysis of HCEC showed that WIN blocked subsequent CAP-induced increases in nonselective outward currents. Taken together, CB1 activation by injury-induced release of endocannabinoids such as 2-AG downregulates TRPV1 mediated inflammation and corneal opacification. Such suppression occurs through protein-protein interaction between TRPV1 and CB1 leading to declines in TRPV1 phosphorylation status. CB1 activation of the GTP binding protein, G(i/o) contributes to CB1 mediated TRPV1 dephosphorylation leading to TRPV1 desensitization, declines in TRPV1-induced increases in currents and pro-inflammatory signaling events.
Copyright © 2012 Elsevier Inc. All rights reserved.
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A novel role for activating transcription factor-2 in 15(S)-hydroxyeicosatetraenoic acid-induced angiogenesis.
Zhao T, Wang D, Cheranov SY, Karpurapu M, Chava KR, Kundumani-Sridharan V, Johnson DA, Penn JS, Rao GN
(2009) J Lipid Res 50: 521-33
MeSH Terms: Activating Transcription Factor 2, Cell Differentiation, Cells, Cultured, Collagen, Drug Combinations, Endothelial Cells, Humans, Hydroxyeicosatetraenoic Acids, Laminin, Mitogen-Activated Protein Kinase 8, Models, Biological, Neovascularization, Pathologic, Proteoglycans, Retinal Neovascularization, Retinal Vessels, Signal Transduction, rac1 GTP-Binding Protein, src-Family Kinases
Show Abstract · Added October 9, 2013
To investigate the mechanisms underlying 15(S)-HETE-induced angiogenesis, we have studied the role of the small GTPase, Rac1. We find that 15(S)-HETE activated Rac1 in human retinal microvascular endothelial cells (HRMVEC) in a time-dependent manner. Blockade of Rac1 by adenovirus-mediated expression of its dominant negative mutant suppressed HRMVEC migration as well as tube formation and Matrigel plug angiogenesis. 15(S)-HETE stimulated Src in HRMVEC in a time-dependent manner and blockade of its activation inhibited 15(S)-HETE-induced Rac1 stimulation in HRMVEC and the migration and tube formation of these cells as well as Matrigel plug angiogenesis. 15(S)-HETE stimulated JNK1 in Src-Rac1-dependent manner in HRMVEC and adenovirus-mediated expression of its dominant negative mutant suppressed the migration and tube formation of these cells and Matrigel plug angiogenesis. 15(S)-HETE activated ATF-2 in HRMVEC in Src-Rac1-JNK1-dependent manner and interference with its activation via adenovirus-mediated expression of its dominant negative mutant abrogated migration and tube formation of HRMVEC and Matrigel plug angiogenesis. In addition, 15(S)-HETE-induced MEK1 stimulation was found to be dependent on Src-Rac1 activation. Blockade of MEK1 activation inhibited 15(S)-HETE-induced JNK1 activity and ATF-2 phosphorylation. Together, these findings show that 15(S)-HETE activates ATF-2 via the Src-Rac1-MEK1-JNK1 signaling axis in HRMVEC leading to their angiogenic differentiation.
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15(S)-HETE production in human retinal microvascular endothelial cells by hypoxia: Novel role for MEK1 in 15(S)-HETE induced angiogenesis.
Bajpai AK, Blaskova E, Pakala SB, Zhao T, Glasgow WC, Penn JS, Johnson DA, Rao GN
(2007) Invest Ophthalmol Vis Sci 48: 4930-8
MeSH Terms: Adenoviridae, Arachidonate 15-Lipoxygenase, Basement Membrane, Cell Movement, Cells, Cultured, Chromatography, High Pressure Liquid, Endothelium, Vascular, Enzyme Inhibitors, Genetic Vectors, Humans, Hydroxyeicosatetraenoic Acids, Hypoxia, MAP Kinase Kinase 1, Mitogen-Activated Protein Kinase 1, Mitogen-Activated Protein Kinase 3, Mitogen-Activated Protein Kinase 8, Phosphorylation, Retinal Neovascularization, Retinal Vessels, Reverse Transcriptase Polymerase Chain Reaction, Time Factors, p38 Mitogen-Activated Protein Kinases
Show Abstract · Added October 9, 2013
PURPOSE - To examine for the expression of 15-lipoxygenase 1 (15-LOX1) and 15-LOX2 in human retinal microvascular endothelial cells (HRMVECs) and study the role of arachidonic acid metabolites of these enzymes in angiogenesis.
METHODS - Quantitative RT-PCR and reverse-phase HPLC analyses were used to determine 15-LOX1/2 expression and their arachidonic acid metabolites in HRMVECs. The role of MEK1 in 15(S)-HETE-induced angiogenesis was studied using HRMVEC migration, tube formation, and basement membrane matrix plug angiogenesis.
RESULTS - HRMVECs expressed both 15-LOX1 and 15-LOX2. Hypoxia induced the expression of 15-LOX1 and the production of its arachidonic acid metabolites 15(S)-hydroxyeicosatetraenoic acid (15(S)-HETE) and 12(S)-hydroxyeicosatetraenoic acid (12(S)-HETE). 15(S)-HETE stimulated HRMVEC migration and tube formation as potently as 20 ng/mL fibroblast growth factor-2 (FGF-2). In addition, 15(S)-HETE stimulated the phosphorylation of ERK1/2, JNK1, p38 MAPK, and MEK1 in a time-dependent manner in these cells. Inhibition of MEK1 by pharmacologic and dominant-negative mutant approaches attenuated 15(S)-HETE-induced phosphorylation of ERK1/2 and JNK1 but not p38 MAPK. Blockade of ERK1/2 and JNK1 activation suppressed 15(S)-HETE-induced HRMVEC migration and tube formation and basement membrane matrix plug angiogenesis. Inhibition of p38 MAPK attenuated 15(S)-HETE-induced HRMVEC migration only. Inhibition of MEK1 also blocked 15(S)-HETE-induced HRMVEC migration and tube formation and basement membrane matrix plug angiogenesis.
CONCLUSIONS - These results suggest that hypoxia, through the induction of 15-LOX1 expression, leads to the production of 15(S)-HETE in HRMVECs. In addition, 15(S)-HETE, through MEK1-dependent activation of ERK1/2 and JNK1, stimulates the angiogenic differentiation of HRMVECs and basement membrane matrix plug angiogenesis.
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22 MeSH Terms
Heregulin-dependent delay in mitotic progression requires HER4 and BRCA1.
Muraoka-Cook RS, Caskey LS, Sandahl MA, Hunter DM, Husted C, Strunk KE, Sartor CI, Rearick WA, McCall W, Sgagias MK, Cowan KH, Earp HS
(2006) Mol Cell Biol 26: 6412-24
MeSH Terms: Animals, BRCA1 Protein, Breast Neoplasms, Epithelial Cells, ErbB Receptors, Exons, G2 Phase, Gene Expression Regulation, Neoplastic, HeLa Cells, Humans, Mammary Glands, Animal, Mice, Mitogen-Activated Protein Kinase 8, Mitogen-Activated Protein Kinase 9, Mitosis, Neuregulin-1, RNA, Messenger, Receptor, ErbB-2, Receptor, ErbB-4, Tumor Cells, Cultured
Show Abstract · Added March 5, 2014
HER4 expression in human breast cancers correlates with a positive prognosis. While heregulin inhibits the growth of HER4-positive breast cancer cells, it does so by undefined mechanisms. We demonstrate that heregulin-induced HER4 activity inhibits cell proliferation and delays G(2)/M progression of breast cancer cells. While investigating pathways of G(2)/M delay, we noted that heregulin increased the expression of BRCA1 in a HER4-dependent, HER2-independent manner. Induction of BRCA1 by HER4 occurred independently of the cell cycle. Moreover, BRCA1 expression was elevated in HER4-postive human breast cancer specimens. Heregulin stimulated c-Jun N-terminal kinase (JNK), and pharmacologic inhibition of JNK impaired heregulin-enhanced expression of BRCA1 and mitotic delay; inhibition of Erk1/2 did not. Knockdown of BRCA1 with small interfering RNA in a human breast cancer cell line interfered with HER4-mediated mitotic delay. Heregulin/HER4-dependent mitotic delay was examined further with an isogenic pair of mouse mammary epithelial cells (MECs) derived from mice harboring homozygous LoxP sites flanking exon 11 of BRCA1, such that one cell line expressed BRCA1 while the other cell line, after Cre-mediated excision, did not. BRCA1-positive MECs displayed heregulin-dependent mitotic delay; however, the isogenic BRCA1-negative MECs did not. These results suggest that heregulin-mediated growth inhibition in HER4-postive breast cancer cells requires BRCA1.
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20 MeSH Terms
Role of NF-kappa B in cell survival and transcription of latent membrane protein 1-expressing or Epstein-Barr virus latency III-infected cells.
Cahir-McFarland ED, Carter K, Rosenwald A, Giltnane JM, Henrickson SE, Staudt LM, Kieff E
(2004) J Virol 78: 4108-19
MeSH Terms: Apoptosis, B-Lymphocytes, Cell Line, Cell Survival, Gene Expression Profiling, Genes, Viral, Herpesvirus 4, Human, Humans, Mitogen-Activated Protein Kinase 8, Mitogen-Activated Protein Kinases, NF-kappa B, Nitriles, Organic Chemicals, Sulfones, Transcription, Genetic, Viral Matrix Proteins, Virus Latency, p38 Mitogen-Activated Protein Kinases
Show Abstract · Added March 5, 2014
Epstein-Barr virus (EBV) latency III infection converts B lymphocytes into lymphoblastoid cell lines (LCLs) by expressing EBV nuclear and membrane proteins, EBNAs, and latent membrane proteins (LMPs), which regulate transcription through Notch and tumor necrosis factor receptor pathways. The role of NF-kappa B in LMP1 and overall EBV latency III transcriptional effects was investigated by treating LCLs with BAY11-7082 (BAY11). BAY11 rapidly and irreversibly inhibited NF-kappa B, decreased mitochondrial membrane potential, induced apoptosis, and altered LCL gene expression. BAY11 effects were similar to those of an NF-kappa B inhibitor, Delta N-I kappa B alpha, in effecting decreased JNK1 expression and in microarray analyses. More than 80% of array elements that decreased with Delta N-I kappa B alpha expression decreased with BAY11 treatment. Newly identified NF-kappa B-induced, LMP1-induced, and EBV-induced genes included pleckstrin, Jun-B, c-FLIP, CIP4, and I kappa B epsilon. Of 776 significantly changed array elements, 134 were fourfold upregulated in EBV latency III, and 74 were fourfold upregulated with LMP1 expression alone, whereas only 28 were more than fourfold downregulated by EBV latency III. EBV latency III-regulated gene products mediate cell migration (EBI2, CCR7, RGS1, RANTES, MIP1 alpha, MIP1 beta, CXCR5, and RGS13), antigen presentation (major histocompatibility complex proteins and JAW1), mitogen-activated protein kinase pathway (DUSP5 and p62Dok), and interferon (IFN) signaling (IFN-gamma R alpha, IRF-4, and STAT1). Comparison of EBV latency III LCL gene expression to immunoglobulin M (IgM)-stimulated B cells, germinal-center B cells, and germinal-center-derived lymphomas clustered LCLs with IgM-stimulated B cells separately from germinal-center cells or germinal-center lymphoma cells. Expression of IRF-2, AIM1, ASK1, SNF2L2, and components of IFN signaling pathways further distinguished EBV latency III-infected B cells from IgM-stimulated or germinal-center B cells.
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18 MeSH Terms