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High-density lipoproteins (HDLs) represent a family of particles characterized by the presence of apolipoprotein A-I (apoA-I) and by their ability to transport cholesterol from peripheral tissues back to the liver. In addition to this function, HDLs display pleiotropic effects including antioxidant, anti-apoptotic, anti-inflammatory, anti-thrombotic or anti-proteolytic properties that account for their protective action on endothelial cells. Vasodilatation via production of nitric oxide is also a hallmark of HDL action on endothelial cells. Endothelial cells express receptors for apoA-I and HDLs that mediate intracellular signalling and potentially participate in the internalization of these particles. In this review, we will detail the different effects of HDLs on the endothelium in normal and pathological conditions with a particular focus on the potential use of HDL therapy to restore endothelial function and integrity.

Background and Purpose— Low levels of low-density lipoprotein-cholesterol (LDL-C) are suspected to be associated with a risk of hemorrhagic transformation after ischemic stroke. We assessed the risk of hemorrhagic transformation after cerebral ischemia/reperfusion in mice with low levels of LDL-C resulting from proprotein convertase subtilisin kexin 9 (PCSK9) deficiency. Methods— PCSK9 −/− and PCSK9 +/+ mice were fed with a high-fat/high-cholesterol (21%/0.15%) diet for 1 month. Plasma lipids were measured using colorimetric assays. PCSK9 −/− and PCSK9 +/+ mice (n=15 per group) were subjected to a 4-hour intraluminal occlusion of the middle cerebral artery followed by 20 hours of reperfusion. Spontaneous hemorrhagic transformation was assessed by quantification of hemoglobin in ischemic tissue. In vitro, a cell model of blood–brain barrier was used to test endothelial barrier integrity in response to decreasing concentrations of LDL-C from 1 to 0.25g/L in ischemia/reperfusion conditions. Results— PCSK9 −/− mice had lower LDL-C, high-density lipoprotein-cholesterol, and total cholesterol levels than PCSK9 +/+ mice before and after 1 month on the high-fat/high-cholesterol diet. Hemoglobin concentration in ischemic cerebral tissue was not different between PCSK9 −/− and PCSK9 +/+ mice (31.5 [18.9–60.1] and 32.8 [14.7–69.9] ng/mg protein, respectively; P =0.81). Infarct volume was also similar in both groups ( P =0.66). Incubation of human cerebral endothelial cells with decreasing concentrations of LDL-C under ischemia/reperfusion conditions did not alter blood–brain barrier permeability. Conclusions— Low levels of LDL-C did not increase the risk of hemorrhagic transformation after cerebral ischemia/reperfusion in mice. Our observations suggest that PCSK9 inhibition, leading to LDL-C lowering, should not increase hemorrhagic complications after acute ischemic stroke.

G protein-coupled receptors (GPCRs) are well-known drug targets. However, a question mark remains for the more than 100 orphan GPCRs as current deorphanisation strategies failed to identify specific ligands for these receptors. Recent advances have shown that orphan GPCRs may have important functions that are ligand-independent. Orphan GPCRs can modulate the function of well-defined drug targets such as GPCRs with identified ligands and neurotransmitter transporters though physical association with those molecules. Thus, compounds that bind to orphan GPCRs and allosterically regulate the function of the interacting partner or even disrupt the interaction with the latter could become new drugs.

Introduction La proproteine convertase subtilisine/kexine type 9 (PCSK9) est un inhibiteur naturel du recepteur aux LDL. L’inhibition de PCSK9 est une nouvelle therapie prometteuse pour abaisser le LDL cholesterol (LDL-C). Toutefois, quelques etudes suggerent que des taux tres bas de LDL-C pourraient etre associes a une augmentation du risque de transformation hemorragique apres une ischemie/reperfusion cerebrale. Nous avons etudie ce risque de transformation hemorragique a partir d’un modele de souris avec des taux tres abaisses de LDL-C par deletion du gene PCSK9 et soumis a une ischemie/reperfusion cerebrale. Materiel et methodes Des souris deletees pour le gene PCSK9 (PCSK9−/−) et leurs controles (PCSK9++) ont suivi un regime riche en cholesterol pendant un mois, puis le profil lipidique a ete analyse. Le modele d’ischemie/reperfusion cerebrale a ete realise par 4 heures d’occlusion intraluminale de l’artere cerebrale moyenne puis 20 heures de reperfusion. La concentration en hemoglobine dans le tissu cerebral ischemique a ete mesuree par une methode Elisa en ng/mg de proteines totales. Le volume d’infarctus cerebral a ete mesure par le logiciel Image J apres coloration vitale mitochondriale au TTC. Les donnees ont ete representees en mediane [min–max]. Le test statistique non parametrique utilise etait le Mann-Whitney avec un p Resultats Apres regime riche en cholesterol, les souris PCSK9−/− avaient un taux de LDL-C inferieur a celui des souris PCSK9++ (0,20 [0,09–0,35] et 0,33 [0,21–0,53] g/L ; p = 0,0005). Le modele d’ischemie/reperfusion cerebrale a ete realise chez 15 souris PCSK9−/− et 15 souris PCSK9++. Une souris dans chaque groupe est decedee apres l’ischemie cerebrale. Vingt-quatre heures apres l’ischemie/reperfusion cerebrale, la concentration en hemoglobine dans le tissu ischemique etait similaire chez les souris PCSK9−/− et PCSK9++ (4,5 [2,7–8,6] et 4,7 [2,1–10] ng/mg ; p = 0,81). Le volume d’infarctus cerebral n’etait pas different entre les deux groupes de souris (p = 0,66). Discussion Des taux tres abaisses de LDL-C apres deletion du gene PCSK9 n’augmentent pas le risque de transformation hemorragique apres une ischemie/reperfusion cerebrale. Ces resultats confortent la securite d’utilisation des inhibiteurs de PCSK9 chez les patients a risque d’accidents vasculaires cerebraux.