High glucose and insulin inhibit VSMC MKP-1 expression by blocking iNOS via p38 MAPK activation

2000 ◽  
Vol 278 (1) ◽  
pp. C81-C91 ◽  
Author(s):  
Najma Begum ◽  
Louis Ragolia
Keyword(s):  
Insulin Resistance ◽  
Cell Growth ◽  
P38 Mapk ◽  
High Glucose ◽  
Insulin Treatment ◽  
Primary Cultures ◽  
Prolonged Treatment ◽  
Mapk Activation ◽  
Mitogen Activated Protein ◽  
Inos Induction

Our laboratory has recently demonstrated a role for the phosphatidylinositol 3-kinase-mediated inducible NO synthase (iNOS) signaling pathway in acute regulation of insulin-induced mitogen-activated protein phosphatase-1 (MKP-1) expression in primary cultures of rat aortic vascular smooth muscle cells (VSMCs) (N. Begum, L. Ragolia, M. McCarthy, and N. Duddy. J. Biol. Chem. 273: 25164–25170, 1998). We now show that prolonged treatment of VSMCs with 100 nM insulin and high glucose (25 mM) for 12–24 h, to mimic hyperinsulinemia and hyperglycemia, completely blocked MKP-1 mRNA and protein expression in response to subsequent acute insulin treatment. To understand the mechanism of insulin resistance induced by high glucose and insulin, we studied the regulation of iNOS protein induction in these cells. Both high glucose and chronic insulin treatment caused a marked impairment of iNOS induction in response to acute insulin. Blocking of signaling via the p38 mitogen-activated protein kinase (MAPK) pathway by prior treatment for 1 h with SB-203580, a synthetic p38 MAPK inhibitor, completely prevented the inhibition of iNOS induced by high glucose and insulin and restored MKP-1 induction to levels observed with acute insulin treatment. In contrast, PD-98059, a MEK inhibitor, had no effect. Furthermore, high glucose and chronic insulin treatment caused sustained p38 MAPK activation. We conclude 1) that chronic insulin and high glucose-induced insulin resistance is accompanied by marked reductions in both iNOS and MKP-1 inductions due to p38 MAPK activation that leads to excessive cell growth and 2) that p38 MAPK/extracellular signal-regulated kinase pathways regulate iNOS induction, thereby controlling MKP-1 expression, which in turn inactivates MAPKs as a feedback mechanism and inhibits cell growth.

scholarly journals APPL1 mediates adiponectin-stimulated p38 MAPK activation by scaffolding the TAK1-MKK3-p38 MAPK pathway

2011 ◽  
Vol 300 (1) ◽  
pp. E103-E110 ◽  
Author(s):  
Xiaoban Xin ◽  
Lijun Zhou ◽  
Caleb M. Reyes ◽  
Feng Liu ◽  
Lily Q. Dong
Keyword(s):  
Protein Kinase ◽  
P38 Mapk ◽  
Mapk Pathway ◽  
Adaptor Protein ◽  
Mapk Signaling ◽  
Mitogen Activated Protein Kinase ◽  
Scaffolding Protein ◽  
Mapk Activation ◽  
P38 Mapk Pathway ◽  
Mitogen Activated Protein

The adaptor protein APPL1 mediates the stimulatory effect of adiponectin on p38 mitogen-activated protein kinase (MAPK) signaling, yet the underlying mechanism remains unclear. Here we show that, in C2C12 cells, overexpression or suppression of APPL1 enhanced or suppressed, respectively, adiponectin-stimulated p38 MAPK upstream kinase cascade, consisting of transforming growth factor-β-activated kinase 1 (TAK1) and mitogen-activated protein kinase kinase 3 (MKK3). In vitro affinity binding and coimmunoprecipitation experiments revealed that TAK1 and MKK3 bind to different regions of APPL1, suggesting that APPL1 functions as a scaffolding protein to facilitate adiponectin-stimulated p38 MAPK activation. Interestingly, suppressing APPL1 had no effect on TNFα-stimulated p38 MAPK phosphorylation in C2C12 myotubes, indicating that the stimulatory effect of APPL1 on p38 MAPK activation is selective. Taken together, our study demonstrated that the TAK1-MKK3 cascade mediates adiponectin signaling and uncovers a scaffolding role of APPL1 in regulating the TAK1-MKK3-p38 MAPK pathway, specifically in response to adiponectin stimulation.

scholarly journals Different Protein Tyrosine Kinases Are Required for B Cell Antigen Receptor–mediated Activation of Extracellular Signal–Regulated kinase, c-Jun NH2-terminal Kinase 1, and p38 Mitogen-activated Protein Kinase

1998 ◽  
Vol 188 (7) ◽  
pp. 1297-1306 ◽  
Author(s):  
Aimin Jiang ◽  
Andrew Craxton ◽  
Tomohiro Kurosaki ◽  
Edward A. Clark
Keyword(s):  
B Cell ◽  
P38 Mapk ◽  
Tyrosine Kinases ◽  
Protein Tyrosine Kinases ◽  
B Cell Antigen Receptor ◽  
Mapk Activation ◽  
Extracellular Signal Regulated Kinase ◽  
Extracellular Signal ◽  
Mitogen Activated Protein ◽  
Erk2 Activation

B cell antigen receptor (BCR) cross-linking activates three distinct families of nonreceptor protein tyrosine kinases (PTKs): src-family kinases, Syk, and Btk; these PTKs are responsible for initiating downstream events. BCR cross-linking in the chicken DT40 B cell line also activates three distinct mitogen-activated protein kinases (MAPKs): extracellular signal–regulated kinase (ERK)2, c-jun NH2-terminal kinase (JNK)1, and p38 MAPK. To dissect the functional roles of these PTKs in MAPK signaling, activation of MAPKs was examined in various PTK-deficient DT40 cells. BCR-mediated activation of ERK2, although maintained in Lyn-deficient cells, was abolished in Syk-deficient cells and partially inhibited in Btk-deficient cells, indicating that BCR-mediated ERK2 activation requires Syk and that sustained ERK2 activation requires Btk. BCR-mediated JNK1 activation was maintained in Lyn-deficient cells but abolished in both Syk- and Btk-deficient cells, suggesting that JNK1 is activated via a Syk- and Btk-dependent pathway. Consistent with this, BCR-mediated JNK1 activation was dependent on intracellular calcium and phorbol myristate acetate–sensitive protein kinase Cs. In contrast, BCR-mediated p38 MAPK activation was detected in all three PTK-deficient cells, suggesting that no single PTK is essential. However, BCR-mediated p38 MAPK activation was abolished in Lyn/Syk double deficient cells, demonstrating that either Lyn or Syk alone may be sufficient to activate p38 MAPK. Our data show that BCR-mediated MAPK activation is regulated at the level of the PTKs.

scholarly journals Role of Mitogen-Activated Protein Kinases in Myocardial Ischemia-Reperfusion Injury during Heart Transplantation

2012 ◽  
Vol 2012 ◽  
pp. 1-16 ◽  
Author(s):  
Giuseppe Vassalli ◽  
Giuseppina Milano ◽  
Tiziano Moccetti
Keyword(s):  
Heart Transplantation ◽  
Organ Transplantation ◽  
P38 Mapk ◽  
Cold Storage ◽  
Organ Procurement ◽  
Ischemia Reperfusion ◽  
Solid Organ ◽  
Mapk Activation ◽  
Mitogen Activated Protein

In solid organ transplantation, ischemia/reperfusion (IR) injury during organ procurement, storage and reperfusion is an unavoidable detrimental event for the graft, as it amplifies graft inflammation and rejection. Intracellular mitogen-activated protein kinase (MAPK) signaling pathways regulate inflammation and cell survival during IR injury. The four best-characterized MAPK subfamilies are the c-Jun NH2-terminal kinase (JNK), extracellular signal- regulated kinase-1/2 (ERK1/2), p38 MAPK, and big MAPK-1 (BMK1/ERK5). Here, we review the role of MAPK activation during myocardial IR injury as it occurs during heart transplantation. Most of our current knowledge regarding MAPK activation and cardioprotection comes from studies of preconditioning and postconditioning in nontransplanted hearts. JNK and p38 MAPK activation contributes to myocardial IR injury after prolonged hypothermic storage. p38 MAPK inhibition improves cardiac function after cold storage, rewarming and reperfusion. Small-molecule p38 MAPK inhibitors have been tested clinically in patients with chronic inflammatory diseases, but not in transplanted patients, so far. Organ transplantation offers the opportunity of starting a preconditioning treatment before organ procurement or during cold storage, thus modulating early events in IR injury. Future studies will need to evaluate combined strategies including p38 MAPK and/or JNK inhibition, ERK1/2 activation, pre- or postconditioning protocols, new storage solutions, and gentle reperfusion.

Targeting p38 MAPK inhibits multiple myeloma cell growth in the bone marrow milieu

Blood ◽  
2003 ◽  
Vol 101 (2) ◽  
pp. 703-705 ◽  
Author(s):  
Teru Hideshima ◽  
Masaharu Akiyama ◽  
Toshiaki Hayashi ◽  
Paul Richardson ◽  
Robert Schlossman ◽  
...  
Keyword(s):  
Multiple Myeloma ◽  
Bone Marrow ◽  
Drug Resistance ◽  
Cell Growth ◽  
P38 Mapk ◽  
Myeloma Cell ◽  
Mitogen Activated Protein Kinase ◽  
Necrosis Factor Alpha ◽  
Multiple Myeloma Cell ◽  
Mitogen Activated Protein

p38 mitogen-activated protein kinase (MAPK) is a member of the MAPK family which is activated by cytokines and growth factors, but its role in pathogenesis of multiple myeloma (MM) is unknown. In this study, we demonstrate that the specific p38 MAPK inhibitor VX-745 inhibits interleukin 6 (IL-6) and vascular endothelial growth factor (VEGF) secretion in bone marrow stromal cells (BMSCs), without affecting their viability. Tumor necrosis factor alpha (TNF-α)–induced IL-6 secretion in BMSCs is also inhibited by VX-745. Importantly, VX-745 inhibits both MM cell proliferation and IL-6 secretion in BMSCs triggered by adherence of MM cells to BMSCs, suggesting that it can inhibit paracrine MM cell growth in the BM milieu and overcome cell adhesion–related drug resistance. These studies therefore identify p38 MAPK as a novel therapeutic target to overcome drug resistance and improve patient outcome in MM.

scholarly journals Dehydroepiandrosterone prevents lipid peroxidation and cell growth inhibition induced by high glucose concentration in cultured rat mesangial cells

2000 ◽  
Vol 166 (2) ◽  
pp. 401-406 ◽  
Author(s):  
E Brignardello ◽  
M Gallo ◽  
M Aragno ◽  
R Manti ◽  
E Tamagno ◽  
...  
Keyword(s):  
Lipid Peroxidation ◽  
Cell Growth ◽  
High Glucose ◽  
Glucose Concentration ◽  
Mesangial Cells ◽  
Primary Cultures ◽  
Thiobarbituric Acid ◽  
Secretory Product ◽  
High Glucose Concentration ◽  
Physiological Concentration

The oxidative stress induced by high glucose concentration contributes to tissue damage associated with diabetes, including renal injury. Dehydroepiandrosterone (DHEA), the major secretory product of the human adrenal gland, has been shown to possess a multi-targeted antioxidant activity which is also effective against lipid peroxidation induced by high glucose. In this study we evaluated the effect of DHEA on the growth impairment which high glucose concentration induces in cultured rat mesangial cells. Primary cultures of rat mesangial cells were grown for 10 days in media containing either normal (i.e. 5.6 mmol/l) or high (i.e. 30 mmol/l) concentrations of glucose, without or with DHEA at different concentrations. The impairment of cell growth induced by high glucose was reversed by 100 nmol/l and 500 nmol/l DHEA, which had no effect on mesangial cells cultured in media containing glucose at the normal physiological concentration (5.6 mmol/l). In high-glucose cultured mesangial cells, DHEA also attenuated the lipid peroxidation, as measured by thiobarbituric acid reactive substances (TBARS) generation and 4-hydroxynonenal (HNE) concentration, and preserved the cellular content of reduced glutathione as well as the membrane Na+/K+ ATPase activity. The data further support the protective effect of DHEA against oxidative damage induced by high glucose concentrations, and bring into focus its possible effectiveness in preventing chronic complications of diabetes.

scholarly journals The p38 Mitogen-Activated Protein Kinase Signaling Pathway Is Coupled to Toll-Like Receptor 5 To Mediate Gene Regulation in Response to Pseudomonas aeruginosa Infection in Human Airway Epithelial Cells

2007 ◽  
Vol 75 (12) ◽  
pp. 5985-5992 ◽  
Author(s):  
Zhe Zhang ◽  
William Reenstra ◽  
Daniel J. Weiner ◽  
Jean-Pierre Louboutin ◽  
James M. Wilson
Keyword(s):  
Pseudomonas Aeruginosa ◽  
Gene Regulation ◽  
P38 Mapk ◽  
Airway Epithelial Cells ◽  
Mitogen Activated Protein Kinase ◽  
Airway Epithelial ◽  
Toll Like Receptor ◽  
Mapk Activation ◽  
Mitogen Activated Protein ◽  
Toll Like Receptor 5

ABSTRACT In this study, we show that stimulation of human airway epithelial cells (HAECs) by Pseudomonas aeruginosa strain PAO1 induces time- and dose-dependent activation of p38 mitogen-activated protein kinase (MAPK). Activated p38 MAPK stayed in the cytoplasm instead of translocating to the nucleus, as shown by cellular fractionation. p38 MAPK was activated when HAECs were incubated with P. aeruginosa strain PAK and Burkholderia cepacia, while little activation was observed with the isogenic flagellin-free strains PAK/fliC and B. cepacia BC/fliC. The presence of Toll-like receptor 5 (TLR5) in 293 cells mediated PAO1-dependent activation of p38 MAPK, and in HAECs p38 MAPK activation was blocked by the overexpression of a dominant negative TLR5. Two inhibitors of p38 MAPK, SB202190 and SB203580, significantly attenuated PAO1-dependent expression of an NF-κB-dependent luciferase reporter gene, suggesting that p38 MAPK activation is required for full activation of NF-κB-dependent signaling. Microarray analysis of NF-κB target genes revealed up-regulation of multiple genes by PAO1 in HAECs. Reverse transcription-PCR and protein expression analysis were used to show that up-regulation of NF-κB-dependent genes induced by PAO1, such as the genes encoding Cox-2 and interleukin-8, was attenuated by SB203580. These results demonstrate a role for p38 MAPK signaling in gene regulation in response to P. aeruginosa via TLR5.

scholarly journals Effects of ethanol on mitogen-activated protein kinase and stress-activated protein kinase cascades in normal and regenerating liver

1998 ◽  
Vol 334 (3) ◽  
pp. 669-676 ◽  
Author(s):  
Jianping CHEN ◽  
Edward J. N. ISHAC ◽  
Paul DENT ◽  
George KUNOS ◽  
Bin GAO
Keyword(s):  
Protein Kinase ◽  
P38 Mapk ◽  
Ethanol Exposure ◽  
Selective Inhibitor ◽  
Chronic Ethanol ◽  
Mitogen Activated Protein Kinase ◽  
Hepatocyte Proliferation ◽  
Mapk Activation ◽  
Chronic Ethanol Consumption ◽  
Mitogen Activated Protein

To understand the mechanisms by which ethanol inhibits hepatocyte proliferation, we studied the effects of ethanol on p42/44 mitogen-activated protein kinase (MAPK), p38 mitogen-activated protein kinase (p38 MAPK) and c-Jun N-terminal kinase (JNK) in normal and regenerating rat liver. Treatment of rat hepatocytes with 100 mM ethanol in vitro for 16 h prolonged the activation of p42/44 MAPK and p38 MAPK induced by various agonists. Such treatment also increased basal JNK activity, but did not potentiate or prolong agonist-induced JNK activation. Ethanol potentiation of the activation of p42/44 MAPK was abolished by pertussis toxin. In contrast, chronic ethanol consumption in vivo inhibited the activation of p42/44 MAPK, p38 MAPK and JNK induced either by partial hepatectomy or by various agonists. However, both acute and chronic ethanol inhibited hepatocyte proliferation induced by insulin and epidermal growth factor. A selective inhibitor of p42/44 MAPK partially prevented the inhibition of hepatocyte proliferation caused by acute, but not by chronic, ethanol exposure, whereas a selective inhibitor of p38 MAPK further inhibited hepatocyte proliferation under both conditions. These data suggest that acute and chronic ethanol inhibit hepatocyte proliferation by different mechanisms. The effect of acute ethanol may be related to the prolongation of p42/44 MAPK activation, whereas inhibition of hepatocyte proliferation by chronic ethanol may be due to inhibition of p38 MAPK activation.

scholarly journals Loss of Oncogenic H-ras-Induced Cell Cycle Arrest and p38 Mitogen-Activated Protein Kinase Activation by Disruption of Gadd45a

2003 ◽  
Vol 23 (11) ◽  
pp. 3859-3871 ◽  
Author(s):  
Dmitry V. Bulavin ◽  
Oleg Kovalsky ◽  
M. Christine Hollander ◽  
Albert J. Fornace
Keyword(s):  
Cell Cycle ◽  
Amino Acids ◽  
Protein Kinase ◽  
Cell Cycle Arrest ◽  
P38 Mapk ◽  
Mitogen Activated Protein Kinase ◽  
Mapk Activation ◽  
Cycle Arrest ◽  
Mitogen Activated Protein ◽  
P53 Activation

ABSTRACT The activation of p53 is a guardian mechanism to protect primary cells from malignant transformation; however, the details of the activation of p53 by oncogenic stress are still incomplete. In this report we show that in Gadd45a −/− mouse embryo fibroblasts (MEF), overexpression of H-ras activates extracellular signal-regulated kinase (ERK) and c-Jun N-terminal kinase (JNK) but not p38 kinase, and this correlates with the loss of H-ras-induced cell cycle arrest (premature senescence). Inhibition of p38 mitogen-activated protein kinase (MAPK) activation correlated with the deregulation of p53 activation, and both a p38 MAPK chemical inhibitor and the expression of a dominant-negative p38α inhibited p53 activation in the presence of H-ras in wild-type MEF. p38, but not ERK or JNK, was found in a complex with Gadd45 proteins. The region of interaction was mapped to amino acids 71 to 96, and the central portion (amino acids 71 to 124) of Gadd45a was required for p38 MAPK activation in the presence of H-ras. Our results indicate that this Gadd45/p38 pathway plays an important role in preventing oncogene-induced growth at least in part by regulating the p53 tumor suppressor.

scholarly journals Cytokine Activation of p38 Mitogen-Activated Protein Kinase and Apoptosis Is Opposed by alpha-4 Targeting of Protein Phosphatase 2A for Site-Specific Dephosphorylation of MEK3

2007 ◽  
Vol 27 (12) ◽  
pp. 4217-4227 ◽  
Author(s):  
Todd D. Prickett ◽  
David L. Brautigan
Keyword(s):  
Protein Kinase ◽  
P38 Mapk ◽  
Protein Phosphatase ◽  
Protein Phosphatase 2A ◽  
Phosphorylation Site ◽  
Mitogen Activated Protein Kinase ◽  
Mapk Activation ◽  
Tnf Α ◽  
Mitogen Activated Protein ◽  
Phosphatase 2A

ABSTRACT alpha-4 is an essential gene and is a dominant antiapoptotic factor in various tissues that is a regulatory subunit for type 2A protein phosphatases. A multiplexed phosphorylation site screen revealed that knockdown of alpha-4 by small interfering RNA (siRNA) increased p38 mitogen-activated protein kinase (MAPK) and c-Jun phosphorylation without changes in JNK or ERK. FLAG-alpha-4 coprecipitated hemagglutinin-MEK3 plus endogenous protein phosphatase 2A (PP2A) and selectively enhanced dephosphorylation of Thr193, but not Ser189, in the activation loop of MEK3. Overexpression of alpha-4 suppressed p38 MAPK activation in response to tumor necrosis factor alpha (TNF-α). The alpha-4 dominant-negative domain (DND) (residues 220 to 340) associated with MEK3, but not PP2A, and its overexpression sensitized cells to activation of p38 MAPK by TNF-α and interleukin-1β, but not by ansiomycin or sorbitol. The response was diminished by nocodazole or by siRNA knockdown of the Opitz syndrome protein Mid1 that binds alpha-4 to microtubules. Interference by alpha-4 DND or alpha-4 siRNA increased caspase 3/7 activation in response to TNF-α. Growth of transformed cells in soft agar was enhanced by alpha-4 and suppressed by alpha-4 DND. The results show that alpha-4 targets PP2A activity to MEK3 to suppress p38 MAPK activation by cytokines, thereby inhibiting apoptosis and anoikis.

MAP kinases in lung endothelial permeability induced by microtubule disassembly

2005 ◽  
Vol 289 (1) ◽  
pp. L75-L84 ◽  
Author(s):  
Anna A. Birukova ◽  
Konstantin G. Birukov ◽  
Boris Gorshkov ◽  
Feng Liu ◽  
Joe G. N. Garcia ◽  
...  
Keyword(s):  
P38 Mapk ◽  
Actin Polymerization ◽  
Map Kinases ◽  
Endothelial Permeability ◽  
Barrier Dysfunction ◽  
Mapk Activation ◽  
Mapk Cascades ◽  
Extracellular Signal ◽  
Mitogen Activated Protein ◽  
Barrier Regulation

Lung endothelial barrier function is regulated by multiple signaling pathways, including mitogen-activated protein kinases (MAPK) extracellular signal-regulated kinases (ERK) 1/2 and p38. We have recently shown involvement of microtubule (MT) disassembly in endothelial cell (EC) barrier failure. In this study, we examined potential involvement of ERK1/2 and p38 MAPK in lung EC barrier dysfunction associated with MT disassembly. MT inhibitors nocodazole (0.2 μM) and vinblastine (0.1 μM) induced sustained activation of Ras-Raf-MEK1/2-ERK1/2 and MKK3/6-p38-MAPKAPK2 MAPK cascades in human and bovine pulmonary EC, as detected by phosphospecific antibodies and in MAPK activation assays. These effects were linked to increased permeability assessed by measurements of transendothelial electrical resistance and cytoskeletal remodeling analyzed by morphometric analysis of EC monolayers. MT stabilization by taxol (5 μM, 1 h) attenuated nocodazole-induced ERK1/2 and p38 MAPK activation and phosphorylation of p38 MAPK substrate 27-kDa heat shock protein and regulatory myosin light chains, the proteins involved in actin polymerization and actomyosin contraction. Importantly, only pharmacological inhibition of p38 MAPK by SB-203580 (20 μM, 1 h) attenuated nocodazole-induced MT depolymerization, actin remodeling, and EC barrier dysfunction, whereas the MEK/ERK1/2 inhibitor U0126 (5 μM, 1 h) exhibited no effect. These data suggest a direct link between p38 MAPK activation, remodeling of MT network, and EC barrier regulation.

Sign in / Sign up

Export Citation Format

Share Document