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Title: Cholesteryl hemiazelate identified in CVD patients causes in vitro and in vivo inflammation
Authors: Domingues, Neuza S. 
Gaifem, Joana
Matthiesen, Rune
Saraiva, Diana P.
Bento, Luís
Marques, André R. A.
Soares, Maria I. L. 
Sampaio, Julio
Klose, Christian
Surma, Michal A.
Almeida, Manuel Lopes de 
Rodrigues, Gustavo
Gonçalves, Pedro Araújo
Ferreira, Jorge
E Melo, Ryan Gouveia
Pedro, Luís Mendes
Simons, Kai 
Melo, Teresa M. V. D. Pinho e 
Cabral, M. Guadalupe
Jacinto, António 
Silvestre, Ricardo
Vaz, Winchil L. C. 
Vieira, Otília V. 
Keywords: cholesteryl hemiesters; cholesteryl hemiazelates; lipidomics; innate inflammatory responses; atherosclerosis
Issue Date: Sep-2023
Publisher: Elsevier
Project: info:eu-repo/grantAgreement/null/null/2022.01305.PTDC/null/LYSosome DYSfunction and cellular Senescence in atherogenesis: is there a link? 
Serial title, monograph or event: Journal of Lipid Research
Volume: 64
Issue: 9
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.
ISSN: 00222275
DOI: 10.1016/j.jlr.2023.100419
Rights: openAccess
Appears in Collections:I&D CQC - Artigos em Revistas Internacionais
FCTUC Química - Artigos em Revistas Internacionais

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