Molecular mechanisms of vascular effects of High-density lipoprotein: alterations in cardiovascular disease

Abstract

Low high-density lipoprotein (HDL)-cholesterol levels are associated with an increased risk of coronary artery disease (CAD) and myocardial infarction, which has triggered the hypothesis that HDL, in contrast to low-density lipoprotein (LDL), acts as an anti-atherogenic lipoprotein. Moreover, experimental studies have identified potential anti-atherogenic properties of HDL, including promotion of macrophage cholesterol efflux and direct endothelial-protective effects of HDL, such as stimulation of endothelial nitric oxide production and repair, anti-apoptotic, anti-inflammatory and anti-thrombotic properties. Studies in gene-targeted mice, however, have also indicated that increasing HDL-cholesterol plasma levels can either limit (e.g. apolipoprotein A-I) or accelerate (e.g. Scavenger receptor class B type I) atherosclerosis. Moreover, vascular effects of HDL have been observed to be heterogenous and are altered in patients with CAD or diabetes, a condition that has been termed 'HDL dysfunction'. These alterations in biological functions of HDL may need to be taken into account for HDL-targeted therapies and considering raising of HDL-cholesterol levels alone is likely not sufficient in this respect. It will therefore be important to further determine, which biological functions of HDL are critical for its anti-atherosclerotic properties, as well as how these can be measured and targeted.

Figure 1. Molecular biosynthesis of HDL

Lipid-free apoA-I is secreted by the liver and intestine and acquires phospholipids and free cholesterol via hepatic and intestinal ABCA-1. Nascent HDL takes up further phospholipids (via PLTP) as well as free cholesterol from peripheral tissues and triglyceride-rich lipoproteins. HDL-associated LCAT esterifies part of the free cholesterol to cholesterol esters, thereby forming the hydrophobic core of the HDL particle (‘HDL maturation’). HDL-associated cholesterol is either directly transferred to the liver via hepatic SR-BI or following CETP-mediated transfer to VLDL/LDL via the hepatic LDL receptor.

Figure 2. Proposed anti-atherogenic effects of HDL in the endothelium

Besides stimulation of macrophage cholesterol transport, HDL has been shown to inhibit endothelial inflammatory activation and to promote endothelial repair. Both effects have been observed to be dependent on endothelial NO production. Furthermore, HDL exerts anti-apoptotic and anti-thrombotic effects that may contribute to its anti-atherogenic capacity.

Figure 3. Signalling pathways mediating the effects of HDL on endothelial NO production

HDL has been shown to stimulate endothelial NO synthase phosphorylation at serine residue 1177 via binding of apoA-I to SR-BI and binding of HDL-associated lysophospholipids to the S1P3 receptor. In addition, HDL-mediated efflux of 7-oxysterols via endothelial ABCG-1 has been observed to inhibit the interaction between eNOS and caveolin, and to prevent the loss of eNOS dimerization induced by reactive oxygen species in the endothelium.

Figure 4. Alterations of the atheroprotective effects of HDL in patients with CAD

Modification of apoA-I by MPO has been shown to impair the macrophage cholesterol efflux capacity of HDL. More recently, accumulation of MDA in HDL from patients with CAD due to an impaired HDL-associated PON1 activity has been observed to stimulate activation of endothelial PKCbeta-II via the LOX-1 receptor. PKCbeta-II activation by HDL from patients with CAD inhibited Akt-dependent phosphorylation of eNOS at serine residue 1177 and increased the inhibitory eNOS phosphorylation at threonine 495, leading to reduced endothelial NO production.