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, High-density Lipoproteins during sepsis: from bench to bedside

T. Sébastien, , vol.1, p.3

, INSERM, UMR 1188 Diabète athérothombose Réunion Océan Indien (DéTROI)

S. Ap-hp, Anesthésie-Réanimation

U. Inserm, Laboratory for Vascular Translational Science Bichat Hospital

S. Ap-hp, Anesthésie-Réanimation

, Laboratoire d'étude de la Microcirculation, Bio-CANVAS: biomarkers in

, CardioNeuroVascular DISEASES » UMRS, vol.942

U. Inserm, Physiopathologie et Epidémiologie des Maladies Respiratoires

, USA. measured by the uptake of a radiolabeled anti-E-selectin antibody. In this in vivo study, reconstituted HDL infusion significantly inhibited IL-1 ? -induced E-selectin expression

, Another study emphasized the fact that rHDLs attenuated adhesion molecule expression in a rodent model of endotoxin shock whereas pretreatment of LPS-injected rats with rHDL limited the expression of P-selectin and ICAM-1 caused by endotoxin in kidney (69)

, Moreover, Zhu et al. have shown in murine macrophages that human serum amyloid A (SAA) dramatically upregulates, the expression and secretion of a group of phospholipases (sPLA2-IIE and sPLA2-V), which are late pro-inflammatory mediators family (74). In this in vitro study using purified HDL, HDL dose-dependently attenuated SAAinduced secretion of both sPLA2-IIE and sPLA2-V. HDLs were also able to attenuate SAAinduced secretion of TLR4-dependent cytokines and chemokines (IL-6, that HDLs stimulate the transcriptional regulator ATF3, which downregulates inflammatory pathways that may in turn decrease the inflammatory response in case of sepsis (73)

, Microvascular vasodilation and endothelium repair

, HDLs have the property to stimulate the endothelial NO synthase (eNOS), which is involved in inhibiting the adhesion of monocytes to the endothelium and promotes microvascular vasodilation (75). This up-regulation of eNOS expression is dependent on SR-B1 receptor

, HDL particles can also stimulate the production of prostacyclin, which is a powerful vasodilator. Kontush et al. have shown that HDL3 sub-fraction had a better capacity to improve NO production than HDL2 because of its enrichment of sphingosine-1-phosphate (S1P), Specific sub-classes of HDL particles bind with different affinity to SR-B1

. Moreover, HDL binding to SR-BI sequentially activates Src family kinases, PI3K, Akt and MAPK. These events lead to increase Rac activity, lamellipodia formation, and ultimately to enhance endothelial cell migration, which improves endothelial repair and monolayer

, HDLs stimulate the endothelial production of NO and prostacyclin which are inhibitors of platelet activation. Furthermore, HDLs prevent platelet hyper-reactivity by limiting intraplatelet cholesterol overload and the interaction of apoA-1 on platelet ABCA1 and SRB1 receptors (79), vol.81

, Antioxidant properties

, The authors performed a co-culture of human aortic endothelial cells and smooth muscle cells pretreated with HDLs isolated from wild-type or PON1-knockout mice. HDLs isolated from PON1 +/+ mice were able to inhibit lipid hydroperoxide (LOOH) accumulation in human LDLs and greatly reduced the amount and chemotactic activity of MCP-1. HDLs from PON1 -/-mice where dysfunctional in these aspects (90). The global antioxidant effect of HDLs is evaluated via their capacity to inhibit LDL oxidation. This property consists in the transfer of oxidized lipids from oxidized LDL (oxLDL) (hydroperoxides and lysophosphatidylcholine) to HDL particles and by the inactivation of oxidized lipids (91), PON1 is able to hydrolyze lipid peroxides and especially oxidized cholesteryl esters and phospholipids, vol.88, p.92

, Anti-apoptotic properties

, In this study, Muller et al. have shown that pretreatment of HMEC-1 cells with HDLs, followed by co-incubation with oxLDLs significantly reduced the time-dependent phosphorylation of IRE1? and elF2?, two major endoplasmic reticulum stress sensors, HDLs exert a protective effect on endothelial cell apoptosis by interfering with both receptormediated death signaling and mitochondrial apoptotic pathways

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