Cholesteryl hemiazelate identified in CVD patients causes in vitro and in vivo inflammation

Neuza Domingues, Joana Gaifem, Rune Matthiesen, Diana P. Saraiva, Luís Bento, André R.A. Marques, Maria I.L. Soares, Julio Sampaio, Christian Klose, Michal A. Surma, Manuel S. Almeida, Gustavo Rodrigues, Pedro Araújo Gonçalves, Jorge Ferreira, Ryan Gouveiae Melo, Luís Mendes Pedro, Kai Simons, Teresa M.V.D. Pinho e Melo, M. Guadalupe Cabral, Antonio JacintoRicardo Silvestre, Winchil Vaz, Otília V. Vieira

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Abstract

Oxidation of PUFAs in LDLs trapped in the arterial intima plays a critical role in atherosclerosis. Though there have been many studies on the atherogenicity of oxidized derivatives of PUFA-esters of cholesterol, the effects of cholesteryl hemiesters (ChEs), the oxidation end products of these esters, have not been studied. Through lipidomics analyses, we identified and quantified two ChE types in the plasma of CVD patients and identified four ChE types in human endarterectomy specimens. Cholesteryl hemiazelate (ChA), the ChE of azelaic acid (n-nonane-1,9-dioic acid), was the most prevalent ChE identified in both cases. Importantly, human monocytes, monocyte-derived macrophages, and neutrophils exhibit inflammatory features when exposed to subtoxic concentrations of ChA in vitro. ChA increases the secretion of proinflammatory cytokines such as interleukin-1β and interleukin-6 and modulates the surface-marker profile of monocytes and monocyte-derived macrophage. In vivo, when zebrafish larvae were fed with a ChA-enriched diet, they exhibited neutrophil and macrophage accumulation in the vasculature in a caspase 1- and cathepsin B-dependent manner. ChA also triggered lipid accumulation at the bifurcation sites of the vasculature of the zebrafish larvae and negatively impacted their life expectancy. We conclude that ChA behaves as an endogenous damage-associated molecular pattern with inflammatory and proatherogenic properties.

Original languageEnglish
Article number100419
JournalJournal Of Lipid Research
Volume64
Issue number9
DOIs
Publication statusPublished - Sept 2023

Keywords

  • atherosclerosis
  • cholesteryl hemiazelates
  • cholesteryl hemiesters
  • innate inflammatory responses
  • lipidomics

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