Cholesteryl hemiazelate identified in CVD patients causes in vitro and in vivo inflammation |
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Affiliation: | 1. iNOVA4Health, NOVA Medical School, Faculdade de Ciências Médicas, (NMS, FCM), Universidade Nova de Lisboa, Lisboa, Portugal;2. Life and Health Sciences Research Institute (ICVS), School of Medicine, University of Minho, Portugal and ICVS/3B''s, PT Government Associate Laboratory, Braga/Guimarães, Portugal;3. Department of Chemistry, Coimbra Chemistry Centre, Institute of Molecular Sciences, University of Coimbra, Coimbra, Portugal;4. Lipotype GmbH, Dresden, Germany;5. Hospital Santa Cruz, Centro Hospitalar de Lisboa Ocidental, Carnaxide, Portugal;6. Department of Vascular Surgery, Hospital de Santa Maria, Centro Hospitalar Universitario Lisboa Norte (CHULN), Lisboa, Portugal |
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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. |
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Keywords: | cholesteryl hemiesters cholesteryl hemiazelates lipidomics innate inflammatory responses atherosclerosis ACS" },{" #name" :" keyword" ," $" :{" id" :" kwrd0040" }," $$" :[{" #name" :" text" ," _" :" acute coronary syndrome CE" },{" #name" :" keyword" ," $" :{" id" :" kwrd0050" }," $$" :[{" #name" :" text" ," _" :" cholesteryl ester ChA" },{" #name" :" keyword" ," $" :{" id" :" kwrd0060" }," $$" :[{" #name" :" text" ," _" :" cholesteryl hemiazelate ChE" },{" #name" :" keyword" ," $" :{" id" :" kwrd0070" }," $$" :[{" #name" :" text" ," _" :" cholesteryl hemiester ChG" },{" #name" :" keyword" ," $" :{" id" :" kwrd0080" }," $$" :[{" #name" :" text" ," _" :" cholesteryl hemiglutarate ChS" },{" #name" :" keyword" ," $" :{" id" :" kwrd0090" }," $$" :[{" #name" :" text" ," _" :" cholesteryl hemisuccinate dpf" },{" #name" :" keyword" ," $" :{" id" :" kwrd0100" }," $$" :[{" #name" :" text" ," _" :" day postfertilization FC" },{" #name" :" keyword" ," $" :{" id" :" kwrd0110" }," $$" :[{" #name" :" text" ," _" :" free cholesterol IL" },{" #name" :" keyword" ," $" :{" id" :" kwrd0120" }," $$" :[{" #name" :" text" ," _" :" interleukin M-CSF" },{" #name" :" keyword" ," $" :{" id" :" kwrd0130" }," $$" :[{" #name" :" text" ," _" :" macrophage colony-stimulating factor MDM" },{" #name" :" keyword" ," $" :{" id" :" kwrd0140" }," $$" :[{" #name" :" text" ," _" :" monocyte-derived macrophage NLRP3" },{" #name" :" keyword" ," $" :{" id" :" kwrd0150" }," $$" :[{" #name" :" text" ," _" :" NOD-like receptor protein 3 oxLDL" },{" #name" :" keyword" ," $" :{" id" :" kwrd0160" }," $$" :[{" #name" :" text" ," _" :" oxidized LDL oxPL" },{" #name" :" keyword" ," $" :{" id" :" kwrd0170" }," $$" :[{" #name" :" text" ," _" :" oxidized phospholipid ROS" },{" #name" :" keyword" ," $" :{" id" :" kwrd0180" }," $$" :[{" #name" :" text" ," _" :" reactive oxygen species SAP" },{" #name" :" keyword" ," $" :{" id" :" kwrd0190" }," $$" :[{" #name" :" text" ," _" :" stable angina pectoris |
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