High-density lipoprotein (HDL) protects against atherosclerosis by upregulation of anti-inflammatory and anti-oxidant pathways

HDL Forum Editor Professor Kerry-Anne Rye highlights new data suggesting an additional mechanism by which high-density lipoprotein (HDL) protects against atherosclerosis, reported by NM Gharavi and co-workers in Arteriosclerosis, Thrombosis and Vascular Biology.

Gharavi NM, Gargalovic PS, Chang I et al. High-density lipoprotein modulates oxidized phospholipid signaling in human endothelial cells from proinflammatory to anti-inflammatory. Arterioscler Thromb Vasc Biol 2007;27:1346-53

Oxidised phospholipids play a key role in the development of atherosclerotic lesions. Present in oxidised low-density lipoprotein (LDL), oxidised phospholipids accumulate in atherosclerotic lesions, leading to activation of endothelial cells and enhanced monocyte/endothelial cell interactions. Recent evidence shows that the presence of oxidised phospholipids is predictive of the presence and progression of atherosclerosis.

It was established a number of years ago that HDL inhibit inflammation in cultured human umbilical vein endothelial cells by reducing the expression of vascular cell adhesion molecule-1 (VCAM-1) and intercellular adhesion molecule-1 (ICAM-1). More recently HDL have also been shown to inhibit VCAM-1 and ICAM-1 expression in cultured human coronary artery endothelial cells (HCAECs). In this elegant study Gharavi et al. have provided convincing evidence that the anti-inflammatory properties of HDL extend beyond the inhibition of adhesion molecule expression by showing that they not only inhibit the pro-inflammatory signalling pathways that are mediated by oxidized phospholipids, but that they also do not have any effect on the ability of oxidized phospholipids to activate the redox-sensitive pathways which protect cells from oxidative stress.

In this study, the researchers investigated the effect of HDL on the pro-inflammatory and pro-oxidant properties induced by the oxidised phospholipids Ox-PAPC (oxidised 1-palmitoyl-2-arachidonyl-sn-3-glycero-phosphorylcholine) and PEIPC (1-palmitoyl-2-(5,5 epoxyisoprostanoyl)-sn-glycero-3-phosphocholine), using human aortic endothelial cells (HAECs) as the experimental model. The studies involved a variety of techniques including real-time polymerase chain reaction, Western analysis and functional studies.

Pretreatment of the HAECs with HDL for one hour, followed by co-treatment with HDL, significantly reduced the induction of genes involved in inflammation, sterol biosynthesis and unfolded protein response (UPR) by Ox-PAPC and PEIPC. In addition, chemotaxis and monocyte binding induced by Ox-PAPC was reduced by HDL. Findings that HDL inhibited the activation of c-Src (a signal transducer that phosphorylates tyrosine residues in proteins and activator of transcription (STAT) 3) within 30 seconds of Ox-PAPC treatment, suggest that degradation of Ox-PAPC is not the mechanism by which HDL inhibits Ox-PAPC signalling. Instead the researchers suggested that HDL differentially regulates certain Ox-PAPC-induced signalling pathways, specifically modulating endothelial nitric oxide synthase phosphorylation (shown to be associated with the inflammatory action of Ox-PAPC), and decreasing superoxide formation. Superoxide is implicated in the increased synthesis of inflammatory molecules, sterol regulatory pathways and UPR. The decrease in superoxide formation may be due in part to the capacity of HDL to prevent endothelial nitric oxide synthase uncoupling, contributing to the anti-oxidant and anti-inflammatory profile of HDL.

The researchers also showed that HDL did not inhibit the activation of redox genes by Ox-PAPC or PEIPC. These redox pathways are important in protecting the cell from the effects of oxidative stress.

In conclusion, these data suggest an additional mechanism by which HDL inhibits atherosclerosis, by directly altering the inflammatory properties of oxidized phospholipids present in atherosclerotic lesions to become anti-inflammatory, as well as maintaining anti-oxidant properties. What makes this study of particular interest is the fact that HDL can inhibit events that are potentially damaging to cells, while simultaneously having no effect on beneficial events. The reasons why (or how) HDL are able to discern processes that are advantageous to cells, and those that are not, are unknown. While the present observations could be due to chance alone, the possibility that this class of lipoproteins has evolved to be selective in terms of function cannot be dismissed. It should, however, be noted that the HDL that were used in these studies were isolated from human plasma and therefore consist of several subpopulations of particles that are structurally and functionally diverse. It would be of particular interest to determine if the beneficial effects that were observed by the investigators are specific to a particular subpopulation of HDL. It also remains to be seen if these effects are apparent in vivo.