APOA1 oxidation is associated to dysfunctional high-density lipoproteins in human abdominal aortic aneurysm

EBioMedicine. 2019 May:43:43-53. doi: 10.1016/j.ebiom.2019.04.012. Epub 2019 Apr 11.

Abstract

Background: High-density lipoproteins (HDL) are a complex mixture of lipids and proteins with vasculoprotective properties. However, HDL components could suffer post-translational modifications (PTMs) under pathological conditions, leading to dysfunctional HDL. We studied whether HDL are modified in abdominal aortic aneurysm (AAA) and the effect on HDL functionality.

Methods: HDL were isolated by ultracentrifugation from AAA tissue (HDL-T) and from plasma of healthy volunteers and then incubated with AAA tissue-conditioned medium (HDL-AAA CM). PTMs from these particles were characterized using Comet-PTM. The ability of HDL-AAA CM for promoting cholesterol efflux was determined ex vivo and in vivo by using J774A.1 [3H]cholesterol-labeled mouse macrophages and after injecting [3H]cholesterol-labeled mouse macrophages and HDL into the peritoneal cavity of wild-type C57BL/6 mice, respectively. Trp50 and Trp108 oxidized forms of APOA1 in HDL incubated with conditioned-medium of activated neutrophils and in plasma of AAA patients and controls were measured by targeted parallel reaction monitoring.

Findings: Oxidation was the most prevalent PTM in apolipoproteins, particularly in APOA1. Trp50 and Trp108 in APOA1 were the residues most clearly affected by oxidation in HDL-T and in HDL-AAA CM, when compared to their controls. In addition, cholesterol efflux was decreased in macrophages incubated with HDL-AAA CM in vitro and a decreased macrophage-to-serum reverse cholesterol transport was also observed in mice injected with HDL-AAA CM. Finally, both oxidized Trp50 and Trp108 forms of APOA1 were increased in HDL incubated with conditioned-medium of activated neutrophils and in plasma of AAA patients in relation to controls.

Interpretation: Oxidative modifications of HDL present in AAA tissue and plasma were closely associated with the loss of vasculoprotective properties of HDL in AAA. FUND: MINECO, ISCiii-FEDER, CIBERDEM, CIBERCV and LA CAIXA.

Keywords: Abdominal aortic aneurysm; Biomarkers; Cholesterol efflux; HDL; Oxidative stress; Proteomics.

MeSH terms

  • Aged
  • Aortic Aneurysm, Abdominal / etiology
  • Aortic Aneurysm, Abdominal / metabolism*
  • Aortic Aneurysm, Abdominal / pathology
  • Apolipoprotein A-I / metabolism*
  • Biomarkers
  • Case-Control Studies
  • Comorbidity
  • Female
  • Humans
  • Immunohistochemistry
  • Lipid Metabolism
  • Lipoproteins, HDL / blood
  • Lipoproteins, HDL / metabolism*
  • Male
  • Middle Aged
  • Oxidation-Reduction*
  • Proteome
  • Proteomics / methods
  • Risk Factors

Substances

  • APOA1 protein, human
  • Apolipoprotein A-I
  • Biomarkers
  • Lipoproteins, HDL
  • Proteome