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In Vitro Analysis of E3 Ubiquitin Ligase Function
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In Vitro Analysis of E3 Ubiquitin Ligase Function

Published on: May 14, 2021

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The SCFFBXO3 ubiquitin E3 ligase regulates inflammation in atherosclerosis

Divay Chandra1, James Londino1, Shaun Alexander1

  • 1Department of Medicine, University of Pittsburgh, Pittsburgh, PA, United States.

Journal of Molecular and Cellular Cardiology
|November 19, 2018
PubMed

Insights

FBXO3, a protein involved in cellular inflammation, promotes atherosclerosis. Inhibiting FBXO3 reduces vascular inflammation and atherosclerosis, offering a potential therapeutic target for this cardiovascular disease.

Area of Science:

  • Cardiovascular Biology
  • Molecular Medicine
  • Immunology

Background:

  • Atherosclerosis is a chronic inflammatory disease driven by lipid accumulation and macrophage dysfunction.
  • Macrophages engulf modified lipoproteins, such as oxidatively modified low-density lipoproteins (OxLDL), promoting inflammation within artery walls.

Purpose of the Study:

  • To investigate the role of FBXO3, a component of the Skp-Cullin-F-box ubiquitin E3 ligase complex, in the inflammatory pathways of atherosclerosis.
  • To determine if targeting FBXO3 can mitigate vascular inflammation and atherosclerosis progression.

Main Methods:

  • Analysis of FBXO3 genetic variants in relation to atherosclerosis development.
  • Immunohistochemical analysis of FBXO3 expression in human carotid plaques.
  • In vitro studies using macrophage cell models to assess the impact of FBXO3 depletion or inhibition on inflammatory responses to OxLDL.

Main Results:

  • A hypofunctioning genetic variant of FBXO3 was associated with reduced atherosclerosis.
  • FBXO3 protein levels were elevated in macrophages from symptomatic atherosclerotic plaques.
  • FBXO3 inhibition or depletion in macrophages decreased pro-inflammatory mediator secretion in response to OxLDL, without affecting OxLDL uptake.

Conclusions:

  • FBXO3 plays a significant role in potentiating vascular inflammation and atherosclerosis.
  • Small molecule inhibition of FBXO3 presents a promising therapeutic strategy for mitigating atherosclerosis.

Keywords:
AtherosclerosisE3 ubiquitin ligaseOxidized low-density lipoproteinVascular inflammation

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