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

Disclosures

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

Proinflammatory HDL

Navab et al.^[29] studied 27 subjects with angiographically documented coronary atherosclerosis and compared them with 31 controls matched for age and sex. The patients had normal lipid levels and their HDL-cholesterol levels were not different to those seen in the controls. When HDL from the patients was added at equal concentrations to cultures of human artery wall cells, together with a standard control LDL, the patient HDL actually increased the resulting monocyte chemotactic activity.

In contrast, HDL from the controls significantly inhibited the LDL-induced monocyte chemotactic activity. In a cell-free assay (in which the ability of the LDL to induce a fluorescent signal, dependent on oxidative changes, was measured in the presence of a test HDL), HDL from the patients enhanced the oxidative signal, and HDL from the controls inhibited the signal. The patients did not have evidence of an acute illness that could explain an acute-phase response.^[7] Navab et al.^[29,30] postulated that the inflammatory properties of HDL were a form of 'chronic acute-phase response', similar to that characterized by C-reactive protein levels in the top tertile of the normal range (i.e. the range that is seen in humans without obvious infection or inflammation such as active rheumatoid arthritis).

Ansell et al.^[3] calculated an 'HDL inflammatory index' for 26 patients with CHD or CHD equivalents who met guidelines for statin therapy but who were not on a statin at the time of enrollment. Blood lipids in these patients prior to therapy were relatively normal (total cholesterol 202 ± 28 mg/dl [5.22 ± 0.70 mmol/l]; HDL cholesterol 57 ± 13 mg/dl [3.87 ± 0.10 mmol/l]; LDL cholesterol 118 ± 24 mg/dl [3.05 ± 0.62 mmol/l]; and triglycerides 125 ± 64 mg/dl [1.41 ± 0.72 mmol/l]).

The HDL inflammatory index was calculated by comparing the monocyte chemotactic activity generated by a standard control LDL in the absence and presence of the test HDL. In the absence of the test HDL, the monocyte chemotactic activity was normalized to 1.0. If the monocyte chemotactic activity increased upon addition of the test HDL, the HDL inflammatory index was >1.0 and the test HDL was classified as proinflammatory. If the monocyte chemotactic activity decreased, the inflammatory index was <1.0 and the HDL was classified as anti-inflammatory.

After the initial blood sample was taken the patients were started on simvastatin (40 mg daily) and, after 6 weeks, a second blood sample was collected. The plasma lipid levels after treatment were significantly improved (total cholesterol 154 ± 22 mg/dl [3.98 ± 0.57 mmol/l]; HDL-cholesterol 61 ± 14 mg/dl [1.58 ± 0.36 mmol/l]; LDL-cholesterol 73 ± 24 mg/dl [1.89 ± 0.62 mmol/l]; triglycerides 99 ± 22 mg/dl [1.12 ± 0.25 mmol/l]). The HDL inflammatory index prior to starting simvastatin was 1.38 ± 0.91 in the patients and 0.38 ± 0.14 in the controls (P = 0.000015). The HDL inflammatory index in the patients decreased from 1.38 ± 0.91 to 1.08 ± 0.71 (P = 0.002) 6 weeks after taking simvastatin. After simvastatin treatment, therefore, the patient's HDL inflammatory index significantly improved, but remained proinflammatory (on average), despite a very significant improvement in plasma lipid levels.^[3]

Ansell et al.^[3] also studied a group of 20 subjects with elevated HDL-cholesterol levels, all of whom were documented to have CHD. The average HDL-cholesterol level for this group was 95 ± 14 mg/dl (2.46 ± 0.36 mmol/l) and the lowest HDL-cholesterol value was 84 mg/dl (2.17 mmol/l). The average total cholesterol level for each patient in this group was 217 ± 35 mg/dl (5.61 ± 0.91 mmol/l); the average LDL-cholesterol level was 108 ± 34 mg/dl (2.80 ± 0.88 mmol/l); and average triglyceride levels were 89 ± 44 mg/dl (1.00 ± 0.50 mmol/l).

The HDL inflammatory index in this high-HDL group was 1.28 ± 0.29, compared with 0.35 ± 0.11 (P = 1.7 × 10^-14) in controls matched for age and sex (a different control group to the one mentioned above). The patients with CHD and high HDL-cholesterol levels, therefore, had proinflammatory HDL. It should be noted that some experimental studies in mice have suggested that serum amyloid A peptides in mice improve efflux capacity of HDL and have antiatherosclerotic effects.^[31]

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Box 1. Interactions of LDL and HDL in Atherosclerosis, and How 'Good Cholesterol' (HDL) can go 'bad' and Increase LDL-Induced Inflammation
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

ABCA-1 = ATP-binding cassette transporter A-1; apoA-I = apolipoprotein A-I; apoB = apolipoprotein B.

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

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

Box 1. Interactions of LDL and HDL in Atherosclerosis, and How 'Good Cholesterol' (HDL) can go 'bad' and Increase LDL-Induced Inflammation
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

ABCA-1 = ATP-binding cassette transporter A-1; apoA-I = apolipoprotein A-I; apoB = apolipoprotein B.

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

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
PPARγ 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.

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