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Integration of flow-dependent endothelial phenotypes by Kruppel-like factor 2
Kush M. Parmar, … , Michael A. Gimbrone Jr., Guillermo García-Cardeña
Kush M. Parmar, … , Michael A. Gimbrone Jr., Guillermo García-Cardeña
Published January 4, 2006
Citation Information: J Clin Invest. 2006;116(1):49-58. https://doi.org/10.1172/JCI24787.
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Research Article Cardiology

Integration of flow-dependent endothelial phenotypes by Kruppel-like factor 2

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Abstract

In the face of systemic risk factors, certain regions of the arterial vasculature remain relatively resistant to the development of atherosclerotic lesions. The biomechanically distinct environments in these arterial geometries exert a protective influence via certain key functions of the endothelial lining; however, the mechanisms underlying the coordinated regulation of specific mechano-activated transcriptional programs leading to distinct endothelial functional phenotypes have remained elusive. Here, we show that the transcription factor Kruppel-like factor 2 (KLF2) is selectively induced in endothelial cells exposed to a biomechanical stimulus characteristic of atheroprotected regions of the human carotid and that this flow-mediated increase in expression occurs via a MEK5/ERK5/MEF2 signaling pathway. Overexpression and silencing of KLF2 in the context of flow, combined with findings from genome-wide analyses of gene expression, demonstrate that the induction of KLF2 results in the orchestrated regulation of endothelial transcriptional programs controlling inflammation, thrombosis/hemostasis, vascular tone, and blood vessel development. Our data also indicate that KLF2 expression globally modulates IL-1β–mediated endothelial activation. KLF2 therefore serves as a mechano-activated transcription factor important in the integration of multiple endothelial functions associated with regions of the arterial vasculature that are relatively resistant to atherogenesis.

Authors

Kush M. Parmar, H. Benjamin Larman, Guohao Dai, Yuzhi Zhang, Eric T. Wang, Sripriya N. Moorthy, Johannes R. Kratz, Zhiyong Lin, Mukesh K. Jain, Michael A. Gimbrone Jr., Guillermo García-Cardeña

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Figure 5

Endothelial transcriptional programs evoked by atheroprotective flow require KLF2 expression.

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Endothelial transcriptional programs evoked by atheroprotective flow req...
(A) Effects of suppressing flow-dependent KLF2 upregulation on gene expression. Cells were treated with either scrambled siRNA or siRNA targeting KLF2 for 24 hours and then placed under static or atheroprotective conditions for an additional 24 hours. Shown are RT-PCR data for the indicated genes. hPGT, human prostaglandin transporter; NOV, nephroblastoma overexpressed gene. (B) Monitoring of the interferon response in HUVECs treated with control or KLF2 siRNAs. Gene expression of 2′-5′-oligoadenylate synthetase (OAS2) or interferon-inducible transmembrane protein 1 (IFITM1) was assessed by TaqMan RT-PCR. As a positive control for the interferon response, HUVECs were incubated with long double-stranded RNA (dsRNA) poly I:C for 24 hours (n = 3). (C) Western blot for proteins in the same samples as represented in A. (D) Surface TM FACS on HUVECs under the indicated conditions. (E) ELISA of CNP from supernatants under the conditions described in A. (F) 15-d-PGJ2 levels in supernatants under the indicated conditions. (G) Histogram (blue bars) of genes binned according to fold regulation under flow. Overlaid on the histogram is a graph showing the percentage of genes within each bin that are KLF2 dependent (red diamonds and trend line). Gray shading indicates the portion of the histogram representing the 74 most highly regulated genes under flow (see text). All data are expressed as mean ± SEM (n = 3). *P < 0.05, **P < 0.01 vs. control; Student’s t test.

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ISSN: 0021-9738 (print), 1558-8238 (online)

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