Platelet-activating factor receptor in GtoPdb v.2023.1

Platelet-activating factor (PAF, 1-O-alkyl-2-acetyl-sn-glycero-3-phosphocholine) is an ether phospholipid mediator associated with platelet coagulation, but also subserves inflammatory roles. The PAF receptor (provisional nomenclature recommended by NC-IUPHAR [38]) is activated by PAF and other suggested endogenous ligands are oxidized phosphatidylcholine [74] and lysophosphatidylcholine [98]. It may also be activated by bacterial lipopolysaccharide [91]

Platelet-activating factor receptor (version 2019.4) in the IUPHAR/BPS Guide to Pharmacology Database

Platelet-activating factor (PAF, 1-O-alkyl-2-acetyl-sn-glycero-3-phosphocholine) is an ether phospholipid mediator associated with platelet coagulation, but also subserves inflammatory roles. The PAF receptor (provisional nomenclature recommended by NC-IUPHAR [37]) is activated by PAF and other suggested endogenous ligands are oxidized phosphatidylcholine [73] and lysophosphatidylcholine [96]. It may also be activated by bacterial lipopolysaccharide [89]

Molecular and functional characterization of polymorphisms in the secreted phospholipase A2 group X gene: relevance to coronary artery disease

Among secreted phospholipases A2 (sPLA2s), human group X sPLA2 (hGX sPLA2) is emerging as a novel attractive therapeutic target due to its implication in inflammatory diseases. To elucidate whether hGX sPLA2 plays a causative role in coronary artery disease (CAD), we screened the human PLA2G10 gene to identify polymorphisms and possible associations with CAD end-points in a prospective study, AtheroGene. We identified eight polymorphisms, among which, one non-synonymous polymorphism R38C in the propeptide region of the sPLA2. The T-512C polymorphism located in the 5′ untranslated region was associated with a decreased risk of recurrent cardiovascular events during follow-up. The functional analysis of the R38C polymorphism showed that it leads to a profound change in expression and activity of hGX sPLA2, although there was no detectable impact on CAD risk. Due to the potential role of hGX sPLA2 in inflammatory processes, these polymorphisms should be investigated in other inflammatory diseases

ROLE DES MEDIATEURS LIPIDIQUES DANS LE DEVELOPPEMENT D'UN FOYER INFLAMMATOIRE AU COURS DE L'ATHEROGENESE

PARIS-BIUSJ-Physique recherche (751052113) / SudocCentre Technique Livre Ens. Sup. (774682301) / SudocSudocFranceF

Phospholipases A2 in atherosclerosis (lipoprotein modifying enzymes and biomarkers of cardiovascular disease)

Atherosclerosis, the main cause of cardiovascular diseases is a chronic inflammatory disease triggered by modified lipoproteins which are retained in the arterial wall and sustained with the continued recruitment of inflammatory cells. We have studied the genetic regulation of two new biomarkers which target oxidized LDL (lipoprotein associated phospholipase A2; LpPLA2/ PAF-AH and anti-phosphorylcholine (anti-PC) antibodies). We found that the heritability of PAF-AH/Lp-PLA2 is less than previously described and that anti-PC levels are partly influenced by dominance genetics. Endothelial injury/dysfunction is considered as an early initiating step in atherosclerotic lesion formation. We identified unfolded protein response (UPR) as a major signalling pathway induced in endothelial cells incubated with LDL phospholipolyzed by GX sPLA2 (LDL-X). Since calcium chelation prevented UPR activation in our experimental conditions, we hypothesized that Ca2+ release from the endoplasmic reticulum is implicated in this process. In the presence of TMB-8, an ER-Ca2+ stabilizer, we showed that decreasing UPR activation we also diminished the related apoptotic pathways caused by LDL-X in endothelial cells . Finally, we demonstrated the ability of LDL-X to modulate the immune response by promoting the maturation of dendritic cells with subsequent activation of Th1 response, the prevalent and pro-atherogenic response of atheroma T cellsL athérosclérose, cause principale des maladies cardiovasculaire, est une maladie inflammatoire chronique déclenchée par des lipoprotéines modifiées, retenues dans la paroi artérielle, et amplifiée par le recrutement continu de cellules inflammatoires. Nous avons étudié la régulation génétique de deux bio-marqueurs qui ciblent les LDL oxydées (LpPLA2/ PAF-AH et les anticorps anti-phosphorylcholine (anti-PC)). Nous avons montré que le caractère héréditaire de la PAF-AH est moins important que décrit auparavant et que le niveau de l'anti-PC est en partie influencé par l'hérédité. La dysfonction endothéliale est considérée comme une des premières étapes dans l initiation de la lésion athéromateuse. Nous avons identifié la voie UPR (unfolded protein response) comme une voie majeure de signalisation induite dans les cellules endothéliales incubées avec des LDL phospholipolysées par la GX sPLA2 (LDL-X). Puisque la chélation du Ca2+ empêche l activation de la voie UPR, dans nos conditions expérimentales, nous avons émis l hypothèse que la libération du Ca2+ du réticulum endoplasmique était impliquée dans ce processus. En utilisant un stabilisateur du Ca2+, le TMB-8, nous avons mis en évidence la possibilité de diminuer l activation de la voie UPR ainsi que l induction de l apoptose associée en réponse aux LDL-X dans les cellules endothéliales. Enfin, nous avons également démontré la capacité des LDL-X à moduler la réponse immunitaire en favorisant la maturation des cellules dendritiques avec l activation de la réponse Th1 qui est la réponse pro-athérogène des lymphocytes T présents dans la lésion athéromateusePARIS-BIUSJ-Biologie recherche (751052107) / SudocSudocFranceF

Rôle du récepteur du platelet activating factor et des cellules musculaires lisses dans l'initiation et le développement des lésions athéromateuses

PARIS-BIUSJ-Thèses (751052125) / SudocPARIS-BIUSJ-Physique recherche (751052113) / SudocSudocFranceF

The terminal six amino-acids of the carboxy cytoplasmic tail of CD36 contain a functional domain implicated in the binding and capture of oxidized low-density lipoprotein.

CD36, a major adhesion molecule expressed by monocytes/macrophages, plays a key role in the binding and internalization of oxidized low-density lipoprotein (OxLDL). This adhesion molecule, a member of an important scavenger receptor family, contains a very short C-terminal cytoplasmic tail that is known to induce intracellular signalling events. However, the domains on the cytoplasmic tail involved in such signal transduction are unknown. In this study, we have investigated the functional components of the cytoplasmic tail by site-directed mutagenesis coupled with functional OxLDL and monoclonal antibody (mAb) binding studies. Seven truncated or punctual CD36 constructs, localized in the cytoplasmic tail, were produced by site-directed mutagenesis. Each construct was stably expressed in HEK293 cells. We used a quantitative and a qualitative method, labelling OxLDL with either iodine or rhodamine, to determine the functional importance of the cytoplasmic domains in OxLDL internalization. Results indicate that: (1) a deletion of the last amino-acid (construct K472STOP) significantly reduces, compared with wild-type, the binding, internalization and degradation of OxLDL; (2) truncation of the last six amino-acids (construct R467STOP) significantly reduces OxLDL binding; (3) the above two constructs (K472STOP and R467STOP) showed a reduced rate of OxLDL internalization compared with wild-type; (4) the binding and rate of internalization of an anti-CD36 monoclonal antibody (10/5) was not affected by the above mentioned mutants (K472STOP and R467STOP), compared with wild-type. This study shows, for the first time, a specific site on the CD36 cytoplasmic tail that is critical for the binding, endocytosis and targeting of OxLDL