Dysfunctional HDL and atherosclerotic cardiovascular disease

Abstract

High-density lipoproteins (HDLs) protect against atherosclerosis by removing excess cholesterol from macrophages through the ATP-binding cassette transporter A1 (ABCA1) and ATP-binding cassette transporter G1 (ABCG1) pathways involved in reverse cholesterol transport. Factors that impair the availability of functional apolipoproteins or the activities of ABCA1 and ABCG1 could, therefore, strongly influence atherogenesis. HDL also inhibits lipid oxidation, restores endothelial function, exerts anti-inflammatory and antiapoptotic actions, and exerts anti-inflammatory actions in animal models. Such properties could contribute considerably to the capacity of HDL to inhibit atherosclerosis. Systemic and vascular inflammation has been proposed to convert HDL to a dysfunctional form that has impaired antiatherogenic effects. A loss of anti-inflammatory and antioxidative proteins, perhaps in combination with a gain of proinflammatory proteins, might be another important component in rendering HDL dysfunctional. The proinflammatory enzyme myeloperoxidase induces both oxidative modification and nitrosylation of specific residues on plasma and arterial apolipoprotein A-I to render HDL dysfunctional, which results in impaired ABCA1 macrophage transport, the activation of inflammatory pathways, and an increased risk of coronary artery disease. Understanding the features of dysfunctional HDL or apolipoprotein A-I in clinical practice might lead to new diagnostic and therapeutic approaches to atherosclerosis.

Figure 1 |. Particles of HDL and/or its main protein constituent, apolipoprotein A-I, have diverse anti- atherosclerotic influences.

Abbreviations: HDL, high-density lipoprotein; LDL, low-density lipoprotein.

Figure 2 |. Role of HDL in the modulation of coronary atherosclerosis.

HDL protects against atherosclerosis through multiple mechanisms, as illustrated. HDL performs a pivotal role in removing cholesterol from cholesterol-loaded macrophages by binding to ABCA1 and stimulating the process of reverse cholesterol transport. In reverse cholesterol transport, preβ-HDL (HDL-VS) binds to the ABCA1 transporter and initiates cholesterol efflux with the conversion of preβ-HDL (HDL-VS) to HDLα (HDL-S). LCAT catalyses the esterification of cholesterol to CEs and the maturation of HDL to CE-rich mature HDL, which can transport cholesterol back to the liver or exchange CEs for triglycerides with the apolipoprotein B-containing lipoproteins. HDL also enhances the endothelial synthesis of NO, a potent vasodilator, to ameliorate endothelial dysfunction, and might also reduce coronary atherosclerosis by decreasing the expression of adhesion molecules on endothelial cells to reduce inflammation, and by decreasing LDL oxidation. Abbreviations: ABCA1, ATP-binding cassette transporter A1; ABCG1, ATP-binding cassette transporter G1; apoA-I, apolipoprotein A-I; apoB-100, apolipoprotein B-100; CE, cholesteryl ester; HDL, high-density lipoprotein; HDL-L, large HDL particle; HDL-S, small HDL particle; HDL-VL, very large HDL particle; HDL-VS, very small HDL particle; ICAM1, intercellular adhesion molecular 1; LCAT, lecithin-cholesterol acetyltransferase; LDL, low-density lipoprotein; NO, nitric oxide; VCAM1, vascular cell adhesion protein 1.

Figure 3 |. Myeloperoxidase-mediated modification of apoA-I and sterol efflux.

In the absence of myeloperoxidase activity, preβ-HDL (HDL-VS) binds to the ABCA1 transporter and initiates the efflux of cholesterol from macrophage foam cells with the concomitant conversion of preβ-HDL (HDL-VS) to HDLα₄ (HDL-S). Oxidation of apoA-I on multiple residues by the proinflammatory enzyme myeloperoxidase might limit the capacity of HDL or apoA-I to mediate cholesterol efflux from macrophages and thus promote the development of experimental and human atherosclerosis. Abbreviations: ABCA1, ATP-binding cassette transporter A1; ABCG1, ATP-binding cassette transporter G1; apoA-I, apolipoprotein A-I; apoB-100, apolipoprotein B-100; CE, cholesteryl ester; HDL, high-density lipoprotein; HDL-L, large HDL particle; HDL-S, small HDL particle; HDL-VL, very large HDL particle; HDL-VS, very small HDL particle; LCAT, lecithin-cholesterol acetyltransferase; LDL, low-density lipoprotein.

Figure 4 |. Acute-phase HDL.

HDL undergoes substantial modification during an acute-phase response. Inflammatory cytokines induce the hepatic expression of acute-phase SAA and group IIa sPLA₂, which leads to the formation of HDL particles that are relatively enriched in SAA and depleted of apoA-I and phospholipid. Increased oxidative stress during inflammation generates HDL that contains oxidatively modified apoA-I. In addition, HDL remodelling during inflammation generates an abundance of triglycerides and a loss of HDL-associated proteins such as apoA-II, CETP, LCAT, PAF-AH, and PON. Results from studies investigating the effect of inflammation on steps in the reverse cholesterol transport pathway have been conflicting. During inflammation, cellular cholesterol efflux by ABCA1 and ABCG1 might be unchanged, decreased, or increased, and the uptake by SCARB1 of CEs from acute-phase HDL into the liver for subsequent excretion is either decreased or unchanged. Abbreviations: ABCA1, ATP-binding cassette transporter A1; ABCG1, ATP-binding cassette transporter G1; apoA, apolipoprotein A; CE, cholesteryl ester; CETP, cholesterol ester transfer protein; HDL, high-density lipoprotein; LCAT, lecithin-cholesterol acyltransferase; PAF-AH, platelet-activating factor acetylhydrolase; PON, paraoxonase; SAA, serum amyloid A; SCARB1, scavenger receptor class B member 1; sPLA₂, secretory phospholipase A₂; TG, triglyceride.