Regulation of Arterial-Venous Differences in Tumor Necrosis Factor Responsiveness of Endothelial Cells by Anatomic Context

Liu, Meng; Kluger, Martin S.; D’Alessio, Alessio; García‐Cardeña, Guillermo; Pober, Jordan S.

doi:10.2353/ajpath.2008.070603

Cited by 44 publications

(48 citation statements)

References 32 publications

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“…Of note, both RNA and protein levels of KLF2 were greater in AR than NAR BOECs, which would counterindicate a protective role of KLF2 for NAR compared to AR BOECs. As higher KLF2 can sometimes lead to higher ICAM levels [24], the higher KLF2 levels in NAR could account for the higher ICAM levels in NAR than AR noted at some time points after cytokine stimulation.…”

Section: Discussionmentioning

confidence: 99%

Proinflammatory phenotype with imbalance of KLF2 and RelA: Risk of childhood stroke with sickle cell anemia

et al. 2009

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Altered inflammation signaling within the cerebral vasculature may be an important risk factor for stroke in children with sickle cell anemia (SCA). This study examines how differential expression of NFjB/p65 (RelA), KLF2, and other transcription factors may act as switches in inflammation signaling leading to observed differences between non-SCA (NS) African Americans and African Americans with SCA who are either at risk (AR) or not at risk (NAR) of childhood stroke based on occurrence of Circle of Willis disease. Clover/ Transfac analysis was used to identify overrepresented transcription factor binding motifs on genes associated with inflammation. Transcription factor binding motifs for the NFjB family and RFX1 were overrepresented on inflammation signaling gene set analysis. Variations in protein expression were determined by flow cytometry of blood outgrowth endothelial cells (BOECs) from NS, AR, and NAR donors and Western blots of protein extracts from both unstimulated and TNFa/IL1b-stimulated BOECs. BOECs from patients with SCA had more cytoplasmic-derived RelA compared with NS BOECs. Sickle BOECs also had heightened responses to inflammatory stimuli compared with NS BOECs, as shown by increased nuclear RelA, and intracellular adhesion molecule (ICAM) response to TNFa/IL1b stimulation. Multiple control points in RelA signaling were associated with risk of childhood stroke. The ratio of proinflammatory factor RelA to anti-inflammatory factor KLF2 was greater in BOECs from AR donors than NS donors. Group risk of childhood stroke with SCA was greatest among individuals who exhibited increased expression of proinflammatory transcription factors and decreased expression of transcription factors that suppress inflammation. Am. J. Hematol. 85:18-23, 2010. V

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Section: Discussionmentioning

confidence: 99%

Proinflammatory phenotype with imbalance of KLF2 and RelA: Risk of childhood stroke with sickle cell anemia

et al. 2009

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“…Because VCAM1 is a well‐known target of KLF2,40 we investigated whether the downregulation of VCAM1 by SAHA is KLF2 dependent. Given that KLF2 overexpression inhibits TNFα‐mediated induction of the proinflammatory molecule, VCAM1,41 in ECs, it is conceivable that the mechanism for the antiatherosclerotic effect of SAHA is partially exerted through KLF2‐dependent anti‐inflammatory action. The consequent antiatherosclerotic effects accompanying KLF2 upregulation by SAHA may include promoting a set of genes with demonstrated anti‐thrombotic, ‐inflammatory, and ‐proliferative functions 10, 35, 42.…”

Section: Discussionmentioning

confidence: 99%

Suberanilohydroxamic Acid as a Pharmacological Kruppel‐Like Factor 2 Activator That Represses Vascular Inflammation and Atherosclerosis

Yang

Liu

et al. 2017

JAHA

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BackgroundKruppel‐like factor 2 (KLF2) is an important zinc‐finger transcription factor that maintains endothelial homeostasis by its anti‐inflammatory, ‐thrombotic, ‐oxidative, and ‐proliferative effects in endothelial cells. In light of the potent vasoprotective effects of KLF2, modulating KLF2 expression or function could give rise to new therapeutic strategies to treat cardiovascular diseases.Methods and ResultsHigh‐throughput drug screening based on KLF2 promoter luciferase reporter assay was performed to screen KLF2 activators. Real‐time PCR and western blot were used to detect gene and protein expression. Identified KLF2 activator was orally administered to ApoE−/− mice to evaluate anti‐atherosclerotic efficacy. By screening 2400 compounds in the Spectrum library, we identified suberanilohydroxamic (SAHA) acid, also known as vorinostat as a pharmacological KLF2 activator through myocyte enhancer factor 2. We found that SAHA exhibited anti‐inflammatory effects and attenuated monocyte adhesion to endothelial cells inflamed with tumor necrosis factor alpha. We further showed that the inhibitory effect of SAHA on endothelial inflammation and ensuing monocyte adhesion was KLF2 dependent using KLF2‐deficient mouse lung endothelial cells or KLF2 small interfering RNA– depleted human endothelial cells. Importantly, we observed that oral administration of SAHA reduced diet‐induced atherosclerotic lesion development in ApoE−/− mice without significant effect on serum lipid levels.ConclusionsThese results demonstrate that SAHA has KLF2‐dependent anti‐inflammatory effects in endothelial cells and provide the proof of concept that KLF2 activation could be a promising therapeutic strategy for treating atherosclerosis.

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“…In situ in the umbilical cord, transcription factor and p300 coactivator recruitment to the enhancer sequence in the E-selectin promoter was reduced in the artery endothelial cells compared with vein endothelial cells. Within 72 h of in vitro culture, however, the artery and vein endothelial cells became almost indistinguishable in this molecular control of their response to TNFα (Liu et al 2008). Vice versa, Bcl-2-transduced HUVEC can become an integrated part of arterioles, capillaries, and venules in vivo with accompanying vascular subset-specific responses to TNFα.…”

Section: Flexibility Of Endothelial Cells To Adapt To Local Conditionsmentioning

confidence: 99%

“…For example, glomerular endothelial cells gain expression of vWF upon culturing (Satchell et al 2006), whereas vWF is almost absent in this part of the microvascular tree in vivo (Pusztaszeri et al 2006). Recently, Liu et al (2008) demonstrated that in situ human umbilical artery and human umbilical vein endothelial cells (HUVEC) exerted dramatic differences in tumor necrosis factor (TNF)α-mediated E-selectin expression capacity. In situ in the umbilical cord, transcription factor and p300 coactivator recruitment to the enhancer sequence in the E-selectin promoter was reduced in the artery endothelial cells compared with vein endothelial cells.…”

Section: Flexibility Of Endothelial Cells To Adapt To Local Conditionsmentioning

confidence: 99%

Microvascular endothelial cell heterogeneity: general concepts and pharmacological consequences for anti-angiogenic therapy of cancer

2008

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Microvascular endothelial cells display a large degree of heterogeneity in function depending on their location in the vascular tree. The existence of organspecific, microvascular-bed-specific, and even intravascular variations in endothelial cell gene expression emphasizes their high cell-to-cell variability, which is furthermore extremely adaptable to altering conditions. The ability of microvascular endothelial cells to respond dynamically to pathology-related microenvironmental changes is particularly apparent in tumor-growth-associated angiogenesis. An understanding of how they behave, how their behavior varies between and within tumors, and how their behavior is related to responsiveness to drugs is critical for the development of effective anti-angiogenic treatment strategies. In this review, we introduce some general issues concerning organ-imprinted microvascular heterogeneity and highlight the importance of studying microvascular endothelial cell behavior in an in vivo context. This is followed by an overview of state-of-the-art knowledge regarding the nature of the variation in microenvironmental conditions in pre-clinical and clinical tumors and their consequences for tumor endothelial behavior. We provide recent insights into the in vivo molecular activation status of the endothelium and, finally, outline our current understanding of the way that anti-angiogenic drugs affect tumor endothelial cells in relation to their anti-tumor effects.

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Regulation of Arterial-Venous Differences in Tumor Necrosis Factor Responsiveness of Endothelial Cells by Anatomic Context

Cited by 44 publications

References 32 publications

Proinflammatory phenotype with imbalance of KLF2 and RelA: Risk of childhood stroke with sickle cell anemia

Proinflammatory phenotype with imbalance of KLF2 and RelA: Risk of childhood stroke with sickle cell anemia

Suberanilohydroxamic Acid as a Pharmacological Kruppel‐Like Factor 2 Activator That Represses Vascular Inflammation and Atherosclerosis

Microvascular endothelial cell heterogeneity: general concepts and pharmacological consequences for anti-angiogenic therapy of cancer

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