EAS Workshop: How does HDL protect against atherosclerosis?

EAS Workshop: How does HDL protect against atherosclerosis?

 Beyond reverse cholesterol transport, HDL exert a range of potent biological activities that provide protection against atherosclerosis (Fig. 1). Latest findings were reviewed by HDL Forum Editor Professor Kerry-Anne Rye, Heart Research Institute, Sydney, Australia at a Workshop during the 78th Congress of the European Atherosclerosis Society (EAS), Hamburg, Germany.

 

 Anti-inflammatory and anti-oxidant properties of HDL

The anti-inflammatory properties of HDL and their main apolipoprotein, apolipoprotein A-I (apoA-I), are now well established. Not only has HDL been shown to inhibit inflammation in vitro, but studies using experimental animal models have shown that HDL inhibit acute vascular inflammation in vivo. In a study by Nicholls et al (2005), chow-fed rabbits received daily infusions of one of the following: saline; reconstituted HDL containing 25 mg apoA-I and 50 mg of either 1-palmitoyl-2-linoleoyl phosphatidylcholine (PLPC) or 1,2-dipalmitoyl phosphatidylcholine (DPPC); 25 mg lipid-free apoA-I; or 50 mg of either PLPC-small unilamellar vesicles (SUVs) or DPPC-SUVs on each of three consecutive days.  Non-occlusive carotid periarterial collars were implanted at the time of the second dose of treatment. 

 At 48 hours after collar implantation there was a~4-fold increase in vascular wall reactive oxygen species, dense infiltration of the arterial wall by polymorphonuclear leukocytes, and increased endothelial expression of vascular cell adhesion molecule-1 (VCAM‑1) (Fig. 2), intercellular adhesion molecule-1 (ICAM-1), and monocyte chemoattractant protein-1 (MCP-1). 

 However, infusion of reconstituted HDL, apoA-I, and phospholipid-SUVs inhibited these collar-induced early pro-oxidant and proinflammatory changes (1).  A subsequent study showed that the anti-inflammatory properties of apoA-I were impaired by non-enzymatic glycation, attributed to a reduced ability to inhibit nuclear factor-kappaB activation and reactive oxygen species formation (2).

 Effect of HDL on beta-cell function

There is also new evidence that HDL may be involved in maintaining normal beta-cell function. Earlier studies that reported that HDL inhibited beta-cell apoptosis and promoted beta-cell survival (3-5). More recently a study by Fryirs et al (2010) show that HDL, apoA-I and apoA-II increase the insulin-secretory capacity of pancreatic beta-cells.

 Fryirs MA, Barter PJ, Appavaroo M et al. Effects of high-density lipoproteins on pancreatic beta-cell insulin secretion. Arterioscler Thromb Vasc Biol 2010;30:d0110.1161/ATVBAHA.110.207373

 In this in vitro study, Min6 cells and primary islets from rats were incubated in the presence and absence of physiologically relevant concentrations of apoA-I or apoA‑II, in lipid free-form or as a constituent of discoidal reconstituted HDL, or with HDL isolated from human plasma. Cells were incubated in basal glucose (2.8 mmol/L) and high-glucose (25 mmol/L) concentrations. Insulin secretion was measured by radioimmunoassay.

 Lipid-free and lipid-associated apoA-I and apoA-II increased insulin secretion under both basal and high-glucose conditions (Figs. 3-5).

 

 

 

This effect was calcium-dependent. Under high-glucose conditions (but not low-glucose conditions), the effect of apoA-I and apoA-II was also KATP channel and glucose metabolism-dependent.  The ability of lipid-free apoA-I and lipid-free apoA-II to increase insulin secretion was dependent on expression of ATP binding cassette (ABC) transporter A1 and scavenger receptor BI (SR-B1), as well as ABC transporter G1 expression for discoidal HDL.

Taken together, these findings show that HDL, apoA-I and apoA-II increase the insulin-secretory capacity of pancreatic beta-cells. The mechanism of this effect differs under low-glucose versus high-glucose conditions. In the former setting, this may involve a novel signalling pathway, possibly via activation of cyclic AMP, which has been previously shown to increase insulin secretion by calcium-dependent and independent pathways. These data therefore raise the possibility that therapeutic intervention aimed at raising HDL levels may also offer the possibility of improving beta-cell function and glycaemic control, with potential implications for the treatment or prevention of type 2 diabetes.

 Does therapeutic intervention to raise HDL also influence HDL function?

 Niacin is the most effective agent currently available for raising HDL cholesterol levels. Studies show that niacin also influences the profile of HDL particles. After treatment with niacin for 16 weeks, there was an increase in the number of larger atheroprotective HDL2 particles and a corresponding decrease in the number of smaller HDL3 particles.

 In patients with type 2 diabetes, niacin has been shown to have beneficial vasoprotective effects independent of lipid-modifying effects in type 2 diabetes (6). Most recently, niacin was shown to protect against experimentally induced endothelial dysfunction and inhibit vascular inflammation, independent of changes in plasma lipid levels in an animal model.

 Wu BJ, Yan L, Charlton F et al. Evidence that niacin inhibits acute vascular inflammation and improves endothelial dysfunction independent of changes in plasma lipids. Arterioscler Thromb Vasc Biol 2010;30:968-75

 In this study, rabbits were fed a normal chow diet with or without supplementation with niacin (0.6% or 1.2%, weight/weight) for 14 days before insertion of a non-occlusive periarterial carotid collar.  At this time, there were no significant differences in plasma lipid levels (total cholesterol, HDL-cholesterol, triglycerides, non-esterified fatty acids or apoA-I) between the control or niacin groups. 

 After 24 hours, the collar induced acute vascular inflammation (as characterised by increased expression of VCAM-1, ICAM-1 and MCP-1, and extensive intima/media neutrophil infiltration) in the control animals. Among the niacin-treated groups, however, there was attenuation of this response (by ~50% for VCAM-1 and ICAM-1, by ~80% for MCP-1 and by -86% for neutrophil infiltration).  Additionally, the collar induced endothelial dysfunction, as shown by acetylcholine-mediated endothelium-dependent vasorelaxation in carotid artery rings taken from control rabbits. However, in collared carotid artery rings taken from rabbits that received niacin, vasorelaxation was improved relative to what was observed in the collared control animals. Niacin was also shown to protect against endothelial dysfunction induced by myeloperoxidase-derived oxidants such as HOCL.  These beneficial effects were associated with improved vascular redox state and increased vascular content of reduced glutathione, a scavenger of reactive oxygen species.

 Despite the fact that niacin has been in clinical use for over 30 years, the metabolic pathways that it influences have still not been fully defined. The current study therefore provides new insights into the mechanism of action of niacin in vivo. The results of this study show for the first time that niacin markedly inhibits acute vascular inflammation and protects against endothelial dysfunction, by increasing the vascular redox state and scavenging reactive oxygen species. These benefits were independent of any lipid-modifying effects of niacin.

 References

1. Nicholls SJ, Dusting GJ, Cutri B et al. Reconstituted high-density lipoproteins inhibit the acute pro-oxidant and proinflammatory vascular changes induced by a periarterial collar in normocholesterolemic rabbits. Circulation 2005;111:1543-50.

2. Nobécourt E, Tabet F, Lambert G et al. Nonenzymatic glycation impairs the antiinflammatory properties of apolipoprotein A-I. Arterioscler Thromb Vasc Biol 2010;30:766-72.

3. Roehrich ME, Mooser V, Lenain V et al. Insulin-secreting beta-cell dysfunction induced by human lipoproteins. J Biol Chem 2003;278:18368-75.

4. Abderrahmani A, Niederhauser G, Favre D et al. Human high-density lipoprotein particles prevent activation of the JNK pathway induced by human oxidised low-density lipoprotein particles in pancreatic beta cells. Diabetologia 2007;50:1304-14.

5. Rutti S, Ehses JA, Sibler RA et al. Low- and high-density lipoproteins modulate function, apoptosis, and proliferation of primary human and murine pancreatic beta-cells. Endocrinology 2009;150:4521-30.

6. Sorrentino SA, Besler C, Rohrer L et al. Endothelial-vasoprotective effects of high-density lipoprotein are impaired in patients with type 2 diabetes mellitus but are improved after extended-release niacin therapy. Circulation 2010;121:110-22.

 


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