Mechanisms of Disease: Proatherogenic HDL-An Evolving Field

Mohamad Navab; Gattadahalli M Anantharamaiah; Srinivasa T Reddy; Brian J Van Lenten; Benjamin J Ansell; Alan M Fogelman

Nat Clin Pract Endocrinol Metab. 2006;2(9):504-511.

Clinical Implications

Although 3 decades of lipid-altering therapy have targeted LDL-cholesterol levels, the focus of research in this area is now shifting to HDL.^{[32,33,34,35]}

One approach has been to use oral apolipoprotein mimetic peptides. Navab et al.^[36] reported that oral administration of an apoA-I mimetic peptide (D-4F) reduced atherosclerosis in mice without changing plasma cholesterol levels. In these studies, LDL-receptor-null mice on a Western diet (high cholesterol and high fat) and apoE-null mice (which lack apoE and, even on a low-fat diet, have hyperlipidemia and atherosclerotic lesions closely resembling human lesions) on a chow diet were found to have proinflammatory HDL that was converted to anti-inflammatory HDL after oral administration of D-4F. This process did not involve significant changes in HDL-cholesterol or total plasma cholesterol levels.^[36] The mechanism of action of D-4F in mice was reported to involve the formation of preβHDL with improvement in HDL-mediated cholesterol efflux and improvement in reverse cholesterol transport from macrophages in vivo.^[37] Treatment of apoE-null mice and monkeys with a combination of oral D-4F and pravastatin synergistically rendered HDL anti-inflammatory and caused lesion regression in old apoE-null mice.^[38]

The physical characteristics of apoA-I mimetic peptides that cause the sequestration of proinflammatory lipids—which inhibit antioxidant enzymes associated with HDL—are thought to have a key role in their efficacy.^[39] Ou et al.^[40] recently reported that oral D-4F restored endothelium dependent and endothelial nitric oxide synthase dependent vasodilation in direct relationship to the duration of treatment. It was also found to reduce the wall thickness of small arteries in as little as 2 weeks, in LDL-receptor-null mice with pre-existing disease fed a Western diet. D-4F had no effect on total cholesterol or HDL-cholesterol concentrations but it did reduce proinflammatory HDL levels. In addition, plasma myeloperoxidase concentrations were not altered by D-4F, but myeloperoxidase association with apoA-I was reduced, as were the levels of 3-nitrotyrosine in apoA-I.^[40] In LDL-receptor-null mice that also lacked apoA-I, D-4F increased endothelium dependent and endothelial nitric oxide synthase dependent vasodilation, but it did not reduce the thickness of the walls of small arteries as it did in mice with apoA-I.^[40,41]

In addition to apoA-I mimetic peptides, an oral peptide with a sequence from another HDL-associated protein (apoJ) has been shown to render HDL anti-inflammatory in mice and monkeys, and to reduce atherosclerosis in apoE-null mice significantly.^[42] Oral peptides, which are too small to form helical structures, have also been shown to exert the same effects.^[43] The common mechanism by which these different peptides render HDL anti-inflammatory has been postulated to be their common ability to sequester and remove oxidized lipids that inhibit enzymes associated with antioxidant HDL.^[44] This common mechanism has been shown to operate in peptides that are apoA-I mimetics or apoJ mimetics, and also in peptides that are too small to contain a helix like those found in apoA-I and apoJ, and which are not mimics of HDL-associated proteins. Shah and Chyu^[44] recently reviewed the potential use of apolipoprotein mimetic peptides in atherosclerosis management.

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Cite this: Mechanisms of Disease: Proatherogenic HDL-An Evolving Field - Medscape - Sep 01, 2006.

Table 1. Current and Emerging Therapies to Raise Levels and Improve Protective Effects of HDL
Therapy	Effects and mechanism
Lifestyle modifications (diet, exercise, and smoking cessation)	Diet: high correlation between overweight and low HDL levels.
	Exercise: in particular by intense regular physical activity.
	Smoking cessation: high correlation between smoking and low HDL levels
Statins	Raise HDL levels by 5–12%, potentially through reduction in CETP levels, by inhibition of Rho signaling pathway and, through PPARα, increased apoA-I gene transcription and increased apoA-I synthesis. Potentially raise HDL levels by reducing triglyceride levels as well as probably improving HDL function
Fibrates (gemfibrozil, bezafibrate, fenofibrate)	Raise HDL levels by 10–15%, in particular in patients with hypertriglyceridemia. They increase hepatic apoA-I synthesis by increasing apoA-I transcription and augment mRNA stability. Fibrates increase triglyceride catabolism as well, probably improving HDL function
Niacin (including Niaspan^® [Kos Pharmaceuticals, Cranbury, NJ])	Significantly increase HDL levels (15–35%) through reduction in hepatic apoA-I catabolism and reduction in triglyceride synthesis
Cholestyramin or fibrates in combination with niacin and/or statins	Decrease coronary stenosis and clinical events
LXR agonists (GW3965, GlaxoSmithKline, Philadelphia, PA)	In general, these agonists raise HDL but can also raise hepatic triglycerides levels, which might adversely affect HDL function
PPARκ agonists (thiazolidinediones)	Increase apoA-I synthesis; effective in treating patients with multiple metabolic abnormalities
PPARα agonists (518674, Lilly and Company, Indianapolis, IN; GW590735, GlaxoSmithKline; K111, Roche Pharmaceuticals, Basel, Switzerland)	Raise HDL and lowering triglyceride levels; increase hepatic apoA-I synthesis
LXRα–PPARα dual agonists	Increase HDL levels without increasing fatty acid synthase activity and lipogenesis and, therefore, without raising triglyceride levels
CETP inhibitors (JTT-705, Japan Tobacco, Tokyo, Japan; torcetrapib, Pfizer, New York, NY; CETi-1, Avant Immunotherapeutics, Needham, MA)	Cause a 40–100% increase in HDL-cholesterol levels in humans. Inhibit cholesterol ester transfer from HDL to apoB lipoproteins
HDL mimetics: ApoA-I_Milano (ETC-216, Pfizer) HDL mimetic peptides, including D-4F ApoA-I–phospholipids
ApoA-I_Milano: infusion in humans causes lesion regression HDL mimetic peptides: prevent lesion progression and cause regression in apoE-null mice. Increase apoA-I synthesis and preβHDL formation, coupled with increased reverse cholesterol transport. In Phase I testing in humans. ApoA-I–phospholipids: result in a 15% increase in HDL-cholesterol in humans

Abbreviations: apoA-I, apolipoprotein A-I; apoB, apolipoprotein B; apoE, apolipoprotein E; CETP, cholesterol ester transfer protein; LXR, liver X receptor; mRNA, messenger RNA; PPAR, peroxisome proliferative activating receptor.

Sidebar: Box 1. Interactions of LDL and HDL in Atherosclerosis, and How 'Good Cholesterol' (HDL) Can Go 'Bad' and Increase LDL-induced I.nflammation.

Atherosclerosis is caused by LDL-induced inflammation of arteries
ApoB is the main protein in LDL. ApoB binds to matrix molecules in the arteries causing the concentration of LDL to be twice that in the circulation. Oxidation of phospholipids contained in LDL that is trapped in the artery wall is a major cause for LDL-induced inflammation
ABCA-1 is a protein on the surface of cells that interacts with apoA-I to promote cholesterol and phospholipid efflux
ApoA-I is the main protein in HDL. It normally promotes cholesterol efflux but it can be damaged by oxidants impairing its ability to remove cholesterol via ABCA-1. Unlike apoB, apoA-I normally does not bind to matrix molecules in arteries
ApoA-I_Milano is a variant of normal apoA-I that has been found, in some studies, to be superior to normal apoA-I, and, in others, no different from normal apoA-I in promoting cholesterol efflux
A series of antioxidant enzymes are associated with HDL. The activity of these enzymes destroys oxidized lipids but is also inhibited by them. Removing the oxidized lipids initiates a positive feedback loop that results in activation of the enzymes and destruction of the oxidized lipids
Anti-inflammatory HDL is HDL with associated antioxidant enzymes that are sufficiently active to destroy the oxidized lipids derived from LDL, which induce an inflammatory response
Proinflammatory HDL is HDL that has accumulated oxidants derived from an inflammatory reaction, which inhibit the HDL-associated antioxidant enzymes and render apoA-I unable to promote ABCA-1-mediated cholesterol efflux. Oxidant accumulation also causes HDL to promote the formation of LDL-derived oxidized lipids and, hence, become proinflammatory

Abbreviations: ABCA-1, ATP-binding cassette transporter A-1; apoA-I, apolipoprotein A-I; apoB, apolipoprotein B.

Sidebar: Box 2. The Role of Macrophages in Atherosclerosis.

Macrophages are blood monocytes in tissue form
Monocytes are drawn into the artery wall by proteins such as monocyte chemotactic protein 1, which are secreted by artery-wall cells in response to oxidized phospholipids
In tissue-culture models of the artery wall, monocyte chemotactic activity is largely caused by the generation of monocyte chemotactic protein 1
The oxidized phospholipids also cause the artery-wall cells to secrete a potent factor (macrophage-colony-stimulating factor) that causes the monocytes to differentiate into macrophages
Macrophages release potent oxidants, including an enzyme known as myeloperoxidase, that further contribute to the oxidation of LDL-phospholipids
Macrophages have receptors that recognize the oxidized phospholipids in LDL and other components of LDL oxidation. These receptors are collectively called 'scavenger receptors' and are different from the normal LDL receptor in that they are not regulated by the cholesterol content within the macrophage. As a result, oxidized LDL is continuously taken up via these receptors, loading the macrophages with cholesterol. The lipid-engorged macrophages have a foamy appearance and are called 'foam cells'; they are the hallmark of the atherosclerotic lesion. Ultimately, the cholesterol-loaded macrophages in the artery wall die and release their cholesterol, causing pools of cholesterol to accumulate
Lesions rich in cholesterol are vulnerable to rupture or ulceration, leading to blood clots
Regression of atherosclerotic lesions requires transport of the excess cholesterol in the artery wall into the plasma, where it must be transported to the liver and secreted in the bile. Since the function of LDL is to carry cholesterol from the liver to peripheral cells and organs, this process is known as reverse cholesterol transport. HDL and apolipoprotein A-I are the main mediators of this process
The oxidants released by the macrophages can damage apolipoprotein A-I and inhibit its ability to promote reverse cholesterol transport

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