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KLF2 Is a novel transcriptional regulator of endothelial proinflammatory activation.

SenBanerjee S, Lin Z, Atkins GB, Greif DM, Rao RM, Kumar A, Feinberg MW, Chen Z, Simon DI, Luscinskas FW, Michel TM, Gimbrone MA, García-Cardeña G, Jain MK - J. Exp. Med. (2004)

Bottom Line: Therefore, identification of the regulatory factors that mediate the effects of these stimuli on endothelial function is of considerable interest.Finally, our studies implicate recruitment by KLF2 of the transcriptional coactivator cyclic AMP response element-binding protein (CBP/p300) as a unifying mechanism for these various effects.These data implicate KLF2 as a novel regulator of endothelial activation in response to proinflammatory stimuli.

View Article: PubMed Central - PubMed

Affiliation: Cardiovascular Division, Brigham and Women's Hospital, Harvard Medical School, 75 Francis St., Boston, MA 02115, USA.

ABSTRACT
The vascular endothelium is a critical regulator of vascular function. Diverse stimuli such as proinflammatory cytokines and hemodynamic forces modulate endothelial phenotype and thereby impact on the development of vascular disease states. Therefore, identification of the regulatory factors that mediate the effects of these stimuli on endothelial function is of considerable interest. Transcriptional profiling studies identified the Kruppel-like factor (KLF)2 as being inhibited by the inflammatory cytokine interleukin-1beta and induced by laminar shear stress in cultured human umbilical vein endothelial cells. Overexpression of KLF2 in umbilical vein endothelial cells robustly induced endothelial nitric oxide synthase expression and total enzymatic activity. In addition, KLF2 overexpression potently inhibited the induction of vascular cell adhesion molecule-1 and endothelial adhesion molecule E-selectin in response to various proinflammatory cytokines. Consistent with these observations, in vitro flow assays demonstrate that T cell attachment and rolling are markedly attenuated in endothelial monolayers transduced with KLF2. Finally, our studies implicate recruitment by KLF2 of the transcriptional coactivator cyclic AMP response element-binding protein (CBP/p300) as a unifying mechanism for these various effects. These data implicate KLF2 as a novel regulator of endothelial activation in response to proinflammatory stimuli.

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KLF2 expression in endothelial cells in response to biochemcial and biomechanical stimuli. (A) Inhibition of KLF2 by IL-1β. HUVECs were treated with IL-1β (10 U/ml) for the indicated times, and expression was assessed by Taqman assay. *P < 0.05. (B) Induction of KLF2 by LSS. HUVEC monolayers were exposed to laminar flow (10 dynes/cm2) for 24 h, and the relative expression of KLF2 was assessed by Taqman assay. *P < 0.05.
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fig1: KLF2 expression in endothelial cells in response to biochemcial and biomechanical stimuli. (A) Inhibition of KLF2 by IL-1β. HUVECs were treated with IL-1β (10 U/ml) for the indicated times, and expression was assessed by Taqman assay. *P < 0.05. (B) Induction of KLF2 by LSS. HUVEC monolayers were exposed to laminar flow (10 dynes/cm2) for 24 h, and the relative expression of KLF2 was assessed by Taqman assay. *P < 0.05.

Mentions: To better understand how biochemical and biomechanical stimuli modulate endothelial function, high throughput genomic transcriptional profiling studies were undertaken. In one set of experiments, cDNA microarray analysis was performed using mRNA from HUVECs exposed to vehicle or IL-1β for various time periods. In a second set of experiments, mRNA from HUVECs exposed to LSS (10 dynes/cm2 for 24 h) was compared with static (no flow) conditions. Results derived from the study of ∼15,000 genes identified several genes to be differentially regulated by these two stimuli. One of these factors, KLF2, was found to be inhibited by IL-1β treatment and induced by LSS. Using real-time PCR, we verified our transcriptional profiling results. As shown in Fig. 1 A, exposure of HUVECs to IL-1β for 3 h resulted in a 4.7-fold decrease in KLF2 expression. In contrast, KLF2 expression was induced 4.5-fold in endothelial cells exposed to LSS when compared with static (no flow) conditions (Fig. 1 B).


KLF2 Is a novel transcriptional regulator of endothelial proinflammatory activation.

SenBanerjee S, Lin Z, Atkins GB, Greif DM, Rao RM, Kumar A, Feinberg MW, Chen Z, Simon DI, Luscinskas FW, Michel TM, Gimbrone MA, García-Cardeña G, Jain MK - J. Exp. Med. (2004)

KLF2 expression in endothelial cells in response to biochemcial and biomechanical stimuli. (A) Inhibition of KLF2 by IL-1β. HUVECs were treated with IL-1β (10 U/ml) for the indicated times, and expression was assessed by Taqman assay. *P < 0.05. (B) Induction of KLF2 by LSS. HUVEC monolayers were exposed to laminar flow (10 dynes/cm2) for 24 h, and the relative expression of KLF2 was assessed by Taqman assay. *P < 0.05.
© Copyright Policy
Related In: Results  -  Collection

Show All Figures
getmorefigures.php?uid=PMC2211816&req=5

fig1: KLF2 expression in endothelial cells in response to biochemcial and biomechanical stimuli. (A) Inhibition of KLF2 by IL-1β. HUVECs were treated with IL-1β (10 U/ml) for the indicated times, and expression was assessed by Taqman assay. *P < 0.05. (B) Induction of KLF2 by LSS. HUVEC monolayers were exposed to laminar flow (10 dynes/cm2) for 24 h, and the relative expression of KLF2 was assessed by Taqman assay. *P < 0.05.
Mentions: To better understand how biochemical and biomechanical stimuli modulate endothelial function, high throughput genomic transcriptional profiling studies were undertaken. In one set of experiments, cDNA microarray analysis was performed using mRNA from HUVECs exposed to vehicle or IL-1β for various time periods. In a second set of experiments, mRNA from HUVECs exposed to LSS (10 dynes/cm2 for 24 h) was compared with static (no flow) conditions. Results derived from the study of ∼15,000 genes identified several genes to be differentially regulated by these two stimuli. One of these factors, KLF2, was found to be inhibited by IL-1β treatment and induced by LSS. Using real-time PCR, we verified our transcriptional profiling results. As shown in Fig. 1 A, exposure of HUVECs to IL-1β for 3 h resulted in a 4.7-fold decrease in KLF2 expression. In contrast, KLF2 expression was induced 4.5-fold in endothelial cells exposed to LSS when compared with static (no flow) conditions (Fig. 1 B).

Bottom Line: Therefore, identification of the regulatory factors that mediate the effects of these stimuli on endothelial function is of considerable interest.Finally, our studies implicate recruitment by KLF2 of the transcriptional coactivator cyclic AMP response element-binding protein (CBP/p300) as a unifying mechanism for these various effects.These data implicate KLF2 as a novel regulator of endothelial activation in response to proinflammatory stimuli.

View Article: PubMed Central - PubMed

Affiliation: Cardiovascular Division, Brigham and Women's Hospital, Harvard Medical School, 75 Francis St., Boston, MA 02115, USA.

ABSTRACT
The vascular endothelium is a critical regulator of vascular function. Diverse stimuli such as proinflammatory cytokines and hemodynamic forces modulate endothelial phenotype and thereby impact on the development of vascular disease states. Therefore, identification of the regulatory factors that mediate the effects of these stimuli on endothelial function is of considerable interest. Transcriptional profiling studies identified the Kruppel-like factor (KLF)2 as being inhibited by the inflammatory cytokine interleukin-1beta and induced by laminar shear stress in cultured human umbilical vein endothelial cells. Overexpression of KLF2 in umbilical vein endothelial cells robustly induced endothelial nitric oxide synthase expression and total enzymatic activity. In addition, KLF2 overexpression potently inhibited the induction of vascular cell adhesion molecule-1 and endothelial adhesion molecule E-selectin in response to various proinflammatory cytokines. Consistent with these observations, in vitro flow assays demonstrate that T cell attachment and rolling are markedly attenuated in endothelial monolayers transduced with KLF2. Finally, our studies implicate recruitment by KLF2 of the transcriptional coactivator cyclic AMP response element-binding protein (CBP/p300) as a unifying mechanism for these various effects. These data implicate KLF2 as a novel regulator of endothelial activation in response to proinflammatory stimuli.

Show MeSH
Related in: MedlinePlus