Abstract

Circulating levels of soluble lectin-like oxidized low-density lipoprotein receptor-1 (sLOX-1) play an important role in the development and progression of atherosclerosis. We hypothesized that the inflammatory marker C-reactive protein (CRP) might stimulate sLOX-1 release by activating tumor necrosis factor-α converting enzyme (TACE). Macrophages differentiated from THP-1 cells were stimulated with TNF-α and further treated with CRP in the absence or presence of specific inhibitors or small interfering RNA (siRNA). Our results showed that CRP increased sLOX-1 release from activated macrophages in a dose-dependent manner and that these effects were regulated by Fc γ receptor II (FcγRII)-mediated p47(phox) phosphorylation, reactive oxygen species (ROS) production, and TACE activation. CRP also enhanced sLOX-1 release from macrophages derived from peripheral blood mononuclear cells (PBMC) of patients with acute coronary syndrome (ACS). Pretreatment with antibody against FcγRII or with CD32 siRNA, p47(phox) siRNA, apocynin, N-acetylcysteine, tumor necrosis factor-α protease inhibitor 1 (TAPI-1) or TACE siRNA attenuated sLOX-1 release induced by CRP. CRP also elevated serum sLOX-1 levels in a rabbit model of atherosclerosis. Thus, CRP might stimulate sLOX-1 release, and the underlying mechanisms possibly involved FcγRII-mediated p47(phox) phosphorylation, ROS production, and TACE activation.

Highlights

  • Circulating levels of soluble lectin-like oxidized low-density lipoprotein receptor-1 play an important role in the development and progression of atherosclerosis

  • C-reactive protein (CRP) stimulated soluble lectin-like oxidized low-density lipoprotein receptor-1 (sLOX-1) release from macrophages activated by tumor necrosis factor (TNF)-␣

  • Because circulating levels of sLOX-1 play a critical role in the development and progression of atherosclerotic lesions and CRP has been established as an important biomarker of the prognosis of acute coronary syndrome (ACS), we tested our hypothesis that CRP might stimulate sLOX-1 release by activating tumor necrosis factor-␣ converting enzyme (TACE)

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Summary

Introduction

Circulating levels of soluble lectin-like oxidized low-density lipoprotein receptor-1 (sLOX-1) play an important role in the development and progression of atherosclerosis. We hypothesized that the inflammatory marker C-reactive protein (CRP) might stimulate sLOX-1 release by activating tumor necrosis factor-␣ converting enzyme (TACE). Our results showed that CRP increased sLOX-1 release from activated macrophages in a dosedependent manner and that these effects were regulated by Fc ␥ receptor II (Fc␥RII)-mediated p47phox phosphorylation, reactive oxygen species (ROS) production, and TACE activation. Pretreatment with antibody against Fc␥RII or with CD32 siRNA, p47phox siRNA, apocynin, N-acetylcysteine, tumor necrosis factor-␣ protease inhibitor 1 (TAPI-1) or TACE siRNA attenuated sLOX-1 release induced by CRP. CRP might stimulate sLOX-1 release, and the underlying mechanisms possibly involved Fc␥RIImediated p47phox phosphorylation, ROS production, and TACE activation.—Zhao, X. CRP enhances soluble LOX-1 release from macrophages by activating TNF-␣ converting enzyme. TACE is synthesized in a latent form and activated by reactive oxygen species (ROS) before reaching the cell membrane [10, 11].

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