Increased Endothelial Mitogen-Activated Protein Kinase Phosphatase-1 Expression Suppresses Proinflammatory Activation at Sites That Are Resistant to Atherosclerosis

Zakkar, Mustafa; Chaudhury, Hera; Sandvik, Gunhild Falleth; Enesa, Karine; Luong, Le Anh; Simon, Chantal; Mason, Justin C.; Krams, Rob; Clark, Andrew R.; Haskard, Dorian O.; Evans, Paul C.

doi:10.1161/circresaha.108.183913

Cited by 101 publications

(102 citation statements)

References 34 publications

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“…JNK and p38, as targets of DUSP1, have been well characterized in vascular cell types, and our data agree with previous reports showing that, after p38 and JNK activation, DUSP1 is effective in decreasing activation and protecting cells from actin stress fiber formation, which often leads to EC dysfunction (39,48,50). In this regard, our finding that heparin treatment of ECs after DUSP1 knockdown resulted in increased TNF␣-induced pJNK and stress fibers indicates that DUSP1 may be critical for routine modulation of stress fiber levels and their remodeling in ECs.…”

Section: Discussionsupporting

confidence: 92%

Heparin Decreases in Tumor Necrosis Factor α (TNFα)-induced Endothelial Stress Responses Require Transmembrane Protein 184A and Induction of Dual Specificity Phosphatase 1

Farwell

Kanyi

Hamel

et al. 2016

Journal of Biological Chemistry

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Despite the large number of heparin and heparan sulfate binding proteins, the molecular mechanism(s) by which heparin alters vascular cell physiology is not well understood. Studies with vascular smooth muscle cells (VSMCs) indicate a role for induction of dual specificity phosphatase 1 (DUSP1) that decreases ERK activity and results in decreased cell proliferation, which depends on specific heparin binding. The hypothesis that unfractionated heparin functions to decrease inflammatory signal transduction in endothelial cells (ECs) through heparininduced expression of DUSP1 was tested. In addition, the expectation that the heparin response includes a decrease in cytokine-induced cytoskeletal changes was examined. Heparin pretreatment of ECs resulted in decreased TNF␣-induced JNK and p38 activity and downstream target phosphorylation, as identified through Western blotting and immunofluorescence microscopy. Through knockdown strategies, the importance of heparin-induced DUSP1 expression in these effects was confirmed. Quantitative fluorescence microscopy indicated that heparin treatment of ECs reduced TNF␣-induced increases in stress fibers. Monoclonal antibodies that mimic heparin-induced changes in VSMCs were employed to support the hypothesis that heparin was functioning through interactions with a receptor. Knockdown of transmembrane protein 184A (TMEM184A) confirmed its involvement in heparin-induced signaling as seen in VSMCs. Therefore, TMEM184A functions as a heparin receptor and mediates anti-inflammatory responses of ECs involving decreased JNK and p38 activity.For almost 100 years heparin has been used as an anticoagulant. Specific heparin interactions with proteins important in the anti-clotting system are now well understood. Many heparin binding proteins, including quite a few involved in modulating vascular function, inflammation, and angiogenesis, have been identified (reviewed in Ref. 1). The large number of reports indicating evidence of decreased endogenous heparin and heparan sulfates (HS) 3 in atherosclerosis (in model animals and human disease) led to a proposal that decreases in endogenous heparins might be important in the development of atherosclerosis (2). More recent evidence in support of that hypothesis includes increased heparanase expression in atherosclerosis (reviewed in Ref.3) and increased levels of glycocalyx heparan sulfate in regions of the vasculature where laminar flow decreases the likelihood of atherosclerosis development (4).In addition to heparin, heparin binding proteins typically also bind HS chains on HS proteoglycans (HSPGs). Although the carbohydrate backbones of heparin and HS are identical, modifications and sulfation patterns vary. HS chains have fewer sulfate residues per disaccharide and a lower overall charge, but their widespread expression suggests that HS may provide many in vivo functions identified originally as heparin functions (reviewed in Ref. 5). Heparin binding to growth factors modulates their activity and appears to protect them from degradation...

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Section: Discussionsupporting

confidence: 92%

Heparin Decreases in Tumor Necrosis Factor α (TNFα)-induced Endothelial Stress Responses Require Transmembrane Protein 184A and Induction of Dual Specificity Phosphatase 1

Farwell

Kanyi

Hamel

et al. 2016

Journal of Biological Chemistry

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“…Likewise, expression levels of DUSP1, a p38-specific MAPK phosphatase recently reported to dampen endothelial inflammation via p38 inhibition (29), and the two angiogenesis/migration-related genes SEMA3F and TEK/TIE2 were up-regulated by both MEK5D and KLF4 (Fig. 3B).…”

Section: Klf4 Mediates Gene Expression Downstream Of Erk5 In Ecs-mentioning

confidence: 74%

Erk5 Activation Elicits a Vasoprotective Endothelial Phenotype via Induction of Krüppel-like Factor 4 (KLF4)

Ohnesorge

Viemann

Schmidt

et al. 2010

Journal of Biological Chemistry

129

135

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The MEK5/Erk5 MAPK cascade has recently been implicated in the regulation of endothelial integrity and represents a candidate pathway mediating the beneficial effects of laminar flow, a major factor preventing vascular dysfunction and disease. Here we expressed a constitutively active mutant of MEK5 (MEK5D) to study the transcriptional and functional responses to Erk5 activation in human primary endothelial cells. We provide evidence that constitutive Erk5 activation elicits an overall protective phenotype characterized by increased apoptosis resistance and a decreased angiogenic, migratory, and inflammatory potential. This is supported by bioinformatic microarray analysis, which uncovered a statistical overrepresentation of corresponding functional clusters as well as a significant induction of anti-thrombotic, hemostatic, and vasodilatory genes. We identify KLF4 as a novel Erk5 target and demonstrate a critical role of this transcription factor downstream of Erk5. We show that KLF4 expression largely reproduces the protective phenotype in endothelial cells, whereas KLF4 siRNA suppresses expression of various Erk5 targets. Additionally, we show that vasoprotective statins potently induce KLF4 and KLF4-dependent gene expression via activation of Erk5. Our data underscore a major protective function of the MEK5/Erk5/KLF4 module in ECs and implicate agonistic Erk5 activation as potential strategy for treatment of vascular diseases.The vascular endothelium, located at the interface between blood and tissue, fulfills a plethora of important functions, including the supply of nutrients and oxygen to the surrounding tissues as well as regulation of hemostasis and inflammatory responses. Endothelial dysfunction contributes to several diseases including chronic inflammation, hemophilia, thrombosis, and atherosclerosis. Thus, elucidation of the factors and molecular mechanisms that influence endothelial function is essential for the development of novel prophylactic and therapeutic strategies against diseases involving the vascular system. A major determinant influencing endothelial integrity is the hemodynamic force exerted by steady pulsatile blood flow. This force generates a continuous shear stress on the endothelial cells (ECs) 3 in the vessel wall, resulting in gene expression changes that protect the vessel from excessive inflammatory responses and thrombosis and provides an essential survival and quiescence signal for the vascular endothelium (1).Various signaling pathways and transcription factors are involved in perception and mediation of shear stress responses. These include the MEK5/Erk5 mitogen-activated protein kinase (MAPK) pathway (2), which is activated by laminar shear stress in ECs (3). In analogy to the related Erk1/2 MAPK, Erk5 activation is triggered by dual phosphorylation at a TEY consensus motif by a mitogen-activated protein kinase kinase (MAPKK or MEK), which in turn is activated via phosphorylation by a MEK kinase (MEKK or MAP3K) (4). In the case of Erk5, the activating phosphorylation is e...

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“…In the atheroprone regions of the vasculature, sustained activation of the mitogen-activated protein kinase (MAPK), p38, and c-Jun N-terminal kinase-1/2 (JNK-1/2) results in enhanced NF-κB and activator protein-1 transcriptional activity, which subsequently promotes a proinflammatory EC phenotype through induction of adhesion molecules such as vascular cell adhesion molecule-1. 14,67 . Activation of the Nrf2 pathway has been shown to negatively regulate the activity of MAPK signaling by enhancing the catalytic activity of MAPK kinase phosphatases by promoting its reduced form and suppressing the activation of the MAPK kinase 3/6, resulting in the reduced activation of p38 MAPK-mediated signaling.…”

Section: Hypertensionmentioning

confidence: 99%

Nrf2 as an Endothelial Mechanosensitive Transcription Factor

2016

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Increased Endothelial Mitogen-Activated Protein Kinase Phosphatase-1 Expression Suppresses Proinflammatory Activation at Sites That Are Resistant to Atherosclerosis

Cited by 101 publications

References 34 publications

Heparin Decreases in Tumor Necrosis Factor α (TNFα)-induced Endothelial Stress Responses Require Transmembrane Protein 184A and Induction of Dual Specificity Phosphatase 1

Heparin Decreases in Tumor Necrosis Factor α (TNFα)-induced Endothelial Stress Responses Require Transmembrane Protein 184A and Induction of Dual Specificity Phosphatase 1

Erk5 Activation Elicits a Vasoprotective Endothelial Phenotype via Induction of Krüppel-like Factor 4 (KLF4)

Nrf2 as an Endothelial Mechanosensitive Transcription Factor

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