HDL and endothelial protection

Abstract

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.

Figure 1

Different receptors for apoA-I and HDLs and associated intracellular signalling pathways (in red) in the endothelial cell (EC). ABCA1 mediates cholesterol and phospholipid efflux to apoA-I to form nascent discoidal HDL particles. ABCG1 transfers oxidized cholesterol to mature HDL particles. SR-BI, in combination with S1P receptors, mediates various endothelio-protective effects including NO production and induction of survival signalling pathways. Inhibition of NF-κB signalling and activation of Akt represent common pathways downstream to the different HDL receptors for mediation of anti-inflammatory, antioxidant and anti-apoptotic effects of HDLs. S1P receptors are involved in the stabilization of adherens junctions. ABCA1, ABCG1 and F₀F₁-ATPase participate in HDL transport through endothelial cells (transcytosis). The intracellular fate of internalized HDL particles and associated proteins [such as α-1 antitrypsin (AAT)] requires further investigation.

Figure 2

Internalization of HDLs labelled with DiIC18 carbocyanines (red) in HCMEC/D3 cells (immortalized human brain endothelial cells). Nuclei are labelled with DAPI (diaminophenylindole) and vascular endothelial-cadherins are immunostained in green. Labelled HDLs were incubated with endothelial cells and rapidly taken up (visible after 15 min of contact). After 4 h of incubation, HDL particles concentrate in the perinuclear area (as shown here).