Phosphorylation of p38 Mitogen-Activated Protein Kinase Downstream of Bax-Caspase-3 Pathway Leads to Cell Death Induced by High <scp>d</scp>-Glucose in Human Endothelial Cells

Nakagami, Hironori; Morishita, Ryuichi; Yamamoto, Kei; Yoshimura, Shin; Taniyama, Yoshiaki; Aoki, Motokuni; Matsubara, Hiroaki; Kim, Shokei; Kaneda, Yasufumi; Ogihara, Toshio

doi:10.2337/diabetes.50.6.1472

Cited by 150 publications

(113 citation statements)

References 58 publications

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“…Many studies have associated increased levels of cytokines or high glucose levels in the bloodstream with increased p38 activity and endothelial dysfunction (1)(2)(3)(4). The mechanism controlling endothelial dysfunction is not clearly understood.…”

Section: Fig 9 Mek6e-induced Migration and Actin Reorganization Invmentioning

confidence: 99%

“…However, several pathological conditions such as hypertension and hyperglycemia are accompanied by a dysfunctional endothelium characterized by impaired re-endothelialization. These conditions are associated with elevated levels of cytokines such as tumor necrosis factor and transforming growth factor-␤ as well as enhanced activation of p38 (1)(2)(3)(4)(5). Interestingly, high glucose levels present in diabetic patients have also been shown to induce the activation of p38 (1).…”

mentioning

confidence: 99%

“…p38 is a member of the mitogen-activated protein kinase (MAPK) 1 family, which includes extracellular signal-regulated kinase (ERK) and c-Jun NH 2 -terminal kinase. These serine/ threonine protein kinases transmit signals from the membrane to the nucleus (6).…”

mentioning

confidence: 99%

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Activation of p38 Has Opposing Effects on the Proliferation and Migration of Endothelial Cells

McMullen

Bryant

Glembotski

et al. 2005

Journal of Biological Chemistry

136

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Pathological conditions such as hypertension and hyperglycemia as well as abrasions following balloon angioplasty all lead to endothelial dysfunction that impacts disease morbidity. These conditions are associated with the elaboration of a variety of cytokines and increases in p38 activity in endothelial cells. However, the relationship between enhanced p38 activity and endothelial cell function remains poorly understood. To investigate the effect of enhanced p38 MAPK activity on endothelial cell function, we expressed an activated mutant of MEK6 (MEK6E), an upstream regulator of p38. Expression of MEK6E activated p38 and resulted in phosphorylation of its downstream substrate, heat shock protein 27 (Hsp27). Activation of p38 was not sufficient to induce apoptosis; however, it did induce p38-dependent cell cycle arrest. MEK6E expression was sufficient to inhibit ERK phosphorylation triggered by growth factors and integrin engagement. MAPK phosphatase-1 (MKP-1) expression was increased upon p38 activation, and expression of a "substrate-trapping" MKP-1 was sufficient to restore ERK activity. Activation of p38 was sufficient to induce cell migration, which was accompanied by alterations in actin architecture characterized by enhanced lamellipodia. Co-expression of a mutant form of Hsp27, lacking all three phosphorylation sites, reversed MEK6E-induced cell migration and altered the cytoskeletal changes induced by p38 activation. Collectively, these results suggest that cellular decisions regarding migration and proliferation are influenced by p38 activity and that prolonged activation of p38 may result in an anti-angiogenic phenotype that contributes to endothelial dysfunction.

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Section: Fig 9 Mek6e-induced Migration and Actin Reorganization Invmentioning

confidence: 99%

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confidence: 99%

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Activation of p38 Has Opposing Effects on the Proliferation and Migration of Endothelial Cells

McMullen

Bryant

Glembotski

et al. 2005

Journal of Biological Chemistry

136

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“…The p38 MAPK pathway is generally considered to be proapoptotic, and has been shown to be involved in TNF-induced apoptosis [46] and in response to various cellular stressors [45]. Sustained phosphorylation of p38 has been linked to high-glucose induced endothelial cell death [87], and Mycoplasma fermentens-mediated and TLR2/6-dependent apoptosis of HEK293 transfectants [88]. Also, in Mal-deficient macrophages, activation of p38, as one of several affected MAP kinases, occurred with delayed kinetics in response to LPS and bacterial lipopeptides [42], suggesting another level of complexity and interconnectedness of TLR2 downstream pathways.…”

Section: Discussionmentioning

confidence: 99%

Heterodimer‐specific TLR2 stimulation results in divergent functional outcomes in B‐cell precursor acute lymphoblastic leukemia

et al. 2015

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Reports of spontaneous acute lymphoblastic leukemia (ALL) remissions following severe bacterial infections suggest that bacterial components may trigger elimination of ALL. To date, TLR2, which recognizes a broad range of bacterial pathogens through TLR1 or TLR6 heterodimerization, has not been fully evaluated for direct effects on ALL. Studies investigating TLR2 signaling in other tumor cell types utilizing single ligands have yielded contradictory results, and comparative, heterodimer-specific analyses of TLR2 stimulation are lacking. In this study, we report that two well-characterized heterodimer-specific TLR2 ligands, Pam 3 CSK 4 (TLR2/1), and Pam 2 CSK 4 (TLR2/6), induce ALL cell lines and primary ALL samples to upregulate CD40 expression. However, only Pam 3 CSK 4 triggers Caspase-8-mediated apoptosis and sensitizes cells to vincristine-mediated cytotoxicity. Consistent with this result, stimulation of ALL cells through TLR2/1 or TLR2/6 activates Mal, p38 and the NF-κB and PI3K signaling pathways with divergent kinetics that may underlie their distinct downstream effects. Our results reveal a novel branching in downstream responses to heterodimer-specific TLR2 stimulation in ALL cells and emphasize the need for comparative studies to determine differential biological effects observed in specific tumor cells. Based on our results, TLR2/1 ligand Pam 3 CSK 4 possesses potential for generating anti-ALL activity through its direct effects on leukemic blasts.Keywords: CD40 r Caspase-8-mediated apoptotic cell death r Heterodimer-specific TLR2 stimulation r Pediatric acute lymphoblastic leukemia r Signaling kinetics Additional supporting information may be found in the online version of this article at the publisher's web-site IntroductionIt is now widely accepted that tumor remissions induced by the proinflammatory activity of Coley's toxin, which contains various bacterial components, is mediated by the engagement of TollCorrespondence: Dr. Kirk R. Schultz e-mail: kschultz@mail.ubc.ca like receptors (TLRs) on immune cells [1][2][3][4][5]. TLRs are a family of germline-encoded pattern recognition receptors that induce innate and adaptive immune responses after binding pathogenand damage-associated molecular patterns [6][7][8][9][10]. In recent years, many studies have demonstrated that purified TLR ligands exert * These authors contributed equally to this work as senior authors.www.eji-journal.eu Eur. J. Immunol. 2015. 45: 1980-1990 Immunomodulation 1981 potent anti-cancer effects against various types of established tumors in both mice and humans [2,5]. However, while some TLR ligands are currently in clinical trials [11,12], their promising preclinical efficacy as anti-cancer agents has not been consistently observed in the clinic [12]. A greater understanding of the cellular and molecular processes that mediate the beneficial and detrimental outcomes of TLR signaling is needed in order to optimize the translation of this approach. Spontaneous remissions of acute lymphoblastic leukemia (ALL) associated with se...

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“…It has been noted in various studies that hyperglycemia induce endothelium cell death by activating bax-caspase proteases pathway [42].…”

Section: Diabetic Nephropathy and Vascular Endothelial Dysfunctionmentioning

confidence: 99%

Association of HLA Class I and II Antigens with Vitiligo in Egyptian Population

Elgendy¹,

Alshawadfy²,

Ali³

et al. 2016

Mol Enzyme Drug Targ

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Endothelial dysfunction is regarded as an important factor in the pathogenesis of diabetes. Endothelial dysfunction has been posited to play an important role in the pathogenesis of diabetic nephropathy (DN).The vascular complications of diabetes impose a huge burden on the management of this disease. The higher incidence of cardiovascular complications and the unfavorable prognosis among diabetic individuals who develop such complications have been correlated to the hyperglycemia-induced oxidative stress and associated endothelial dysfunction. Both hyperglycemia, as well as the metabolic consequences of glucose dysregulation, are thought to lead to endothelial cell dysfunction. In this regard, endothelial nitric oxide synthase (eNOS) plays a central role in dysfunction. This review will focus on the mechanisms and therapeutics that specifically target endothelial dysfunction in the context of a diabetic setting.

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Phosphorylation of p38 Mitogen-Activated Protein Kinase Downstream of Bax-Caspase-3 Pathway Leads to Cell Death Induced by High d-Glucose in Human Endothelial Cells

Cited by 150 publications

References 58 publications

Activation of p38 Has Opposing Effects on the Proliferation and Migration of Endothelial Cells

Activation of p38 Has Opposing Effects on the Proliferation and Migration of Endothelial Cells

Heterodimer‐specific TLR2 stimulation results in divergent functional outcomes in B‐cell precursor acute lymphoblastic leukemia

Association of HLA Class I and II Antigens with Vitiligo in Egyptian Population

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