TY - JOUR
T1 - Cholesteryl hemiazelate identified in CVD patients causes in vitro and in vivo inflammation
AU - Domingues, Neuza
AU - Gaifem, Joana
AU - Matthiesen, Rune
AU - Saraiva, Diana P.
AU - Bento, Luís
AU - Marques, André R.A.
AU - Soares, Maria I.L.
AU - Sampaio, Julio
AU - Klose, Christian
AU - Surma, Michal A.
AU - Almeida, Manuel S.
AU - Rodrigues, Gustavo
AU - Gonçalves, Pedro Araújo
AU - Ferreira, Jorge
AU - Melo, Ryan Gouveiae
AU - Pedro, Luís Mendes
AU - Simons, Kai
AU - Pinho e Melo, Teresa M.V.D.
AU - Guadalupe Cabral, M.
AU - Jacinto, Antonio
AU - Silvestre, Ricardo
AU - Vaz, Winchil
AU - Vieira, Otília V.
N1 - Funding Information:
supported by FCT through projects UIDB/00313/2020 and UIDP/00313/2020.
Funding Information:
R. S. group has been funded by national funds, through the FCT—project numbers UIDB/50026/2020 and UIDP/ 50026/2020 and 2020.00185. CEECIND to the FCT.
Funding Information:
N. D. was a holder of a PhD fellowship from the FCT (Ref. N◦: SFRH/BD/51877/2012).
Funding Information:
The authors acknowledge the technical support of the Microscopy and Fish Facilities NOVA Medical School. They also acknowledge the UC-NMR facility for obtaining the NMR data (http://www.nmrccc.uc.pt). This work was also supported by the Biobanco-iMM, Lisbon Academic Medical Center, Lisbon, Portugal. This work was financially supported by the Foundation for Science and Technology (FCT) of the Portuguese Ministry of Science and Higher Education through national funds, project reference: 2022.01305.PTDC. The Coimbra Chemistry Centre is Fig. 7. Working model of the proatherogenic properties of ChA. ChA is an end product of cholesteryl linoleate oxidation, generated in the arterial intima. Because of its amphiphilic properties, ChA can be detected in the plasma of CVD patients. The presence of ChA in circulation can imprint an inflammatory phenotype in the circulating monocytes and neutrophils (1), conditioning the immunological response in the arterial intima. ChA promotes the recruitment of innate immune cells, neutrophils, and monocytes into the vasculature (2). Here, neutrophils in the presence of ChA secret IL-1β, which can interfere with monocyte/ macrophage priming. Monocytes differentiated in the presence of ChA are activated, increasing the secretion of inflammatory cytokines: IL-1β, IL-6, and IL-10 (3). In activated macrophages, ChA induces lipid accumulation (foam cells) and lysosomal dysfunction, conferring then the second signal necessary for IL-1β secretion mediated by inflammasome activation (4). IL-1β can initiate a propagation loop of the inflammation, increasing the macrophage secretion of IL-6 and TNF-α. On the other hand, dysfunctional lysosomes will decrease the clearance capacity of macrophages, leading to lipid accumulation in the arterial intima.
Publisher Copyright:
© 2023 THE AUTHORS.
PY - 2023/9
Y1 - 2023/9
N2 - 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.
AB - 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.
KW - atherosclerosis
KW - cholesteryl hemiazelates
KW - cholesteryl hemiesters
KW - innate inflammatory responses
KW - lipidomics
UR - http://www.scopus.com/inward/record.url?scp=85171672894&partnerID=8YFLogxK
U2 - 10.1016/j.jlr.2023.100419
DO - 10.1016/j.jlr.2023.100419
M3 - Article
C2 - 37482218
AN - SCOPUS:85171672894
SN - 0022-2275
VL - 64
JO - Journal of Lipid Research
JF - Journal of Lipid Research
IS - 9
M1 - 100419
ER -