Kruppel-like Factor 4 Regulates Endothelial Inflammation

Hamik, Anne; Lin, Zhiyong; Kumar, Ajay; Balcells, Mercedes; Sinha, Sumita; Katz, Jonathan P.; Feinberg, Mark W.; Gerzsten, Robert E; Edelman, Elazer R.; Jain, Mukesh K.

doi:10.1074/jbc.m700078200

Cited by 337 publications

(252 citation statements)

References 86 publications

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“…This suggests that KLF2 and KLF4 act partially redundant in ECs. This is also supported by a recent study that previously reported induction of established KLF2 targets by KLF4 in ECs (27). Moreover, another study showed a compensatory upregulation of KLF4 upon deletion of one KLF2 allele, which has been suggested to account for the absent endothelial phenotype upon partial KLF2 loss (39).…”

Section: Discussionsupporting

confidence: 74%

“…Thus, our data not only prove that KLF4 is located downstream of Erk5 but also demonstrate that it indeed represents a functionally relevant mediator of Erk5-dependent gene expression in ECs. In agreement with that, KLF4 has previously been identified in a microarray study for flow-activated genes (28) and is known to suppress proinflammatory gene expression in ECs (27). It should be noted, however, that consistent with a study in Erk5-deficient mouse embryonic fibroblasts (26), we additionally identified KLF2 as major factor induced by active MEK5D.…”

Section: Discussionsupporting

confidence: 74%

“…Rather, they inhibit NFB activation at the level of transactivation, which is strongly dependent on co-stimulatory signals such as p38 activation, which affects acetylation of NFB (34) and, importantly, amplifies NFB-induced proinflammatory gene expression in ECs (35). For KLF4, similar conclusions were drawn by Hamik et al (27), who observed that KLF4 expression did not affect NFB binding in band-shift assays in ECs but reduced NFB activity by about 50% in luciferase assays in COS cells. Although the authors did not provide a mechanism, KLF4 has been reported to bind the transcriptional co-activator p300/CBP (41,42), and p300/CBP-mediated acetylation of NFB is required for optimal transactivation of NFB-dependent target genes (43).…”

Section: Discussionsupporting

confidence: 67%

“…ns, not significant. of MEK5D as KLF4 has previously been shown to inhibit proinflammatory gene expression in ECs (27). In this report KLF4 overexpression resulted in decreased TNF-mediated leukocyte adhesion associated with reduced expression of the cell adhesion molecule VCAM1.…”

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

confidence: 61%

“…Besides KLF2, however, we also identified another Krüppel-like factor, KLF4. Interestingly, KLF4 has recently been reported as a shear stress-activated gene and an important regulator of inflammation in ECs (27,28). Thus, KLF4 was a good candidate to mediate at least some of the gene expression downstream of Erk5.…”

Section: Volume 285 • Number 34 • August 20 2010mentioning

confidence: 99%

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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

127

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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Section: Discussionsupporting

confidence: 74%

Section: Discussionsupporting

confidence: 74%

Section: Discussionsupporting

confidence: 67%

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

confidence: 61%

Section: Volume 285 • Number 34 • August 20 2010mentioning

confidence: 99%

See 3 more Smart Citations

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

127

135

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Biochemical‐ and Biophysical‐Induced Barriergenesis in the Blood–Brain Barrier: A Review of Barriergenic Factors for Use in In Vitro Models

Schofield

Rodrigo‐Navarro

Dalby

et al. 2021

Advanced NanoBiomed Research

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Central nervous system (CNS) pathologies are a prevalent problem in aging populations, creating a need to understand the underlying events in these diseases and develop efficient CNS‐targeting drugs. The importance of the blood–brain barrier (BBB) is evident, acting both as a physical barrier to drug entry into the CNS and potentially as the cause or aggravator of CNS diseases. The development of a biomimetic BBB in vitro model is required for the understanding of BBB‐related pathologies and in the screening of drugs targeting the CNS. There is currently great interest in understanding the influence of biochemical and biophysical factors, as these have the potential to greatly improve the barrier function of brain microvascular endothelial cells (BMECs). Recent advances in understanding how these may regulate barriergenesis in BMECs help promote the development of improved BBB in vitro models and therefore novel interventional therapies for pathologies related to its disruption. Herein, an overview of specific biochemical and biomechanical cues in the formation of the BBB, with a focus on in vitro models and how these might recapitulate the BBB function, is provided.

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Role of Krüppel‐like factor 4 in phenotypic switching and proliferation of vascular smooth muscle cells

2010

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SummaryPhenotypic switching and proliferation of vascular smooth muscle cells (VSMCs) are critical components in the development of many vascular proliferation diseases such as atherosclerosis and restenosis after percutaneous coronary interventions. Krü ppel-like factor 4 (KLF4) has been shown to play a key role in VSMC proliferation and differentiation. The focus of this review is to provide an overview for understanding the physiological and pathobiological roles of KLF4 in phenotypic switching and proliferation of VSMCs.

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Kruppel-like Factor 4 Regulates Endothelial Inflammation

Cited by 337 publications

References 86 publications

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

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

Biochemical‐ and Biophysical‐Induced Barriergenesis in the Blood–Brain Barrier: A Review of Barriergenic Factors for Use in In Vitro Models

Role of Krüppel‐like factor 4 in phenotypic switching and proliferation of vascular smooth muscle cells

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