Fluid shear stress regulates the expression of Lectin-like oxidized low density lipoprotein receptor-1 via KLF2-AP-1 pathway depending on its intensity and pattern in endothelial cells

Ji Yoon Lee, Jihwa Chung, Kyoung Hwa Kim, Shung Hyun An, Minsuk Kim, Junbeom Park, Kihwan Kwon

Research output: Contribution to journalArticlepeer-review

20 Scopus citations

Abstract

Background and aims: Vascular endothelial cells (ECs) are exposed to fluid shear stress (FSS), which modulates vascular pathophysiology. Lectin-like oxidized low-density lipoprotein receptor-1 (LOX-1) is crucial in endothelial dysfunction and atherosclerosis. We elucidated the mechanism regulating LOX-1 expression in ECs by FSS. Methods: Human umbilical vein endothelial cells were exposed to laminar shear stress (LSS) of indicated intensities using a unidirectional steady flow, or to oscillatory shear stress (OSS) using a bidirectional disturbed flow. In vivo studies were performed in a mouse model of partial carotid ligation and human pulmonary artery sections. Results: Within ECs, OSS upregulated LOX-1 expression, while LSS (20 dyne/cm2) downregulated it. We confirmed that OSS-induced LOX-1 expression was suppressed when the mechanotransduction was inhibited by knockdown of the mechanosensory complex. In addition, we demonstrated that Kruppel-like factor 2 (KLF2) has an inhibitory role on OSS-induced LOX-1 expression. Next, we determined that activator protein-1 (AP-1) was the key transcription factor inducing LOX-1 expression by OSS, which was inhibited by KLF2 overexpression. To explore whether the intensity of LSS affects LOX-1 expression, we tested three different intensities (20, 60, and 120 dyne/cm2) of LSS. We observed higher LOX-1 expression with high shear stresses of 120 dyne/cm2 compared to 20 and 60 dyne/cm2, with OSS-like KLF2-AP-1 signaling patterns. Furthermore, ECs within disturbed flow regions showed upregulated LOX-1 expression in vivo. Conclusions: We concluded that LOX-1 expression on ECs is regulated via FSS depending on its intensity as well as pattern. Furthermore, this is mediated through the KLF2-AP1 pathway of mechanotransduction.

Original languageEnglish
Pages (from-to)76-88
Number of pages13
JournalAtherosclerosis
Volume270
DOIs
StatePublished - Mar 2018

Bibliographical note

Publisher Copyright:
© 2018

Keywords

  • Activator protein-1
  • Fluid shear stress
  • Kruppel-like factor 2
  • LOX-1
  • Mechanosensory complex
  • Vascular endothelial cells

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