An overview of the pathogenesis of atherosclerosis. The influence of high-density lipoprotein (HDL) and oxidized low-density lipoprotein (oxLDL) on atherosclerosis is one part of the story, as shown in the open circle on the right. However, many other processes impact on arterial health, including additional factors influencing inflammation, oxidation, and the immune response. Proinflammatory HDLs (piHDLs) play a role in each of these processes. EC, endothelial cell; IFNγ, interferon-gamma; IL, interleukin; iNOS, inducible nitric oxide synthase; L, lymphocyte; M, monocyte; MCP-1, monocyte chemotactic protein-1; OxPL, oxidized phospholipid; TNFα, tumor necrosis factor-alpha.

Comparison of the inflammatory indices of high-density lipoproteins (HDLs) isolated from healthy controls (left column) and patients with systemic lupus erythematosus (SLE) (middle column) and rheumatoid arthritis (RA) (right column). Numbers below 1.0 are normal; numbers greater than or equal to 1.0 are proinflammatory. Data are presented as box-and-whisker plots; the ends of each box represent the lowest and highest quartiles, the vertical lines show minimum and maximum values, and horizontal lines in each box indicate median values. Note that inflammatory indices are higher in SLE patients than in healthy controls or RA patients and are higher in RA patients than in healthy controls. Statistical analyses are as follows: SLE versus healthy controls, P < 0.0001; RA versus healthy controls, P = 0.004; and SLE versus RA, P = 0.005. There were 154 individuals in the SLE group, 45 in the RA group, and 74 healthy volunteers. All individuals are female. Data are from [55].

Comparison of normal protective anti-inflammatory high-density lipoproteins (HDLs) (a) to proinflammatory HDLs (b). Normal HDLs are rich in apolipoproteins (yellow ovals) and antioxidant enzymes (white squares). After exposure to pro-oxidants, oxidized lipids, and proteases, proinflammatory HDLs have less lipoprotein and some, such as the major transporter apolipoprotein A-1 (A-1 in the figure), are disabled by the addition of chlorine, nitrogen, and oxygen to protein moieties: A-1 can no longer stabilize paraoxonase-1 (PON1) so PON1 cannot exert its antioxidant enzyme activity. In addition, pro-oxidant acute-phase proteins are added to the particle (serum amyloid A [SAA] and ceruloplasmin) as are oxidized lipids. The figure is based on information in [2] and [41]. apoJ, apolipoprotein J; CE, cholesterol ester; CE-OOH, cholesteryl linoleate hydroperoxide; GSH, glutathione; HPETE, hydroxyeicosatetraenoic acid; HPODE, hydroperoxy-octadecadienoic acid; LCAT, lecithin cholesterol acyltransferase; PAF-AH, platelet-activating acyl hydrolase.

Overview of synthesis, maturation, and disposal of high-density lipoproteins (HDLs). Apolipoprotein A1 (apoA1) is synthesized by the action of ATP-binding cassette transporter AI (ABCA1) in the liver and small intestine and is secreted as immature HDL (imm HDL) particles with large amounts of protein and small amounts of free cholesterol. Macrophages and peripheral tissues also donate free cholesterol and phospholipids to apoA1 to form more immature HDL particles. The action of lecithin cholesterol acyltransferase (LCAT) adds esterified cholesterol to the core of HDLs, leading to mature HDL particles composed of lipoproteins (apoA1 being the most abundant), phospholipids, and cholesterol esters. Cholesterol esters are shuttled to apoB-rich low-density lipoproteins (LDLs) and very-low-density lipoproteins (VLDLs) by the actions of cholesterol ester transfer protein (CETP). Conversely, phospholipids are transferred from LDLs/VLDLs to HDLs by the action of phospholipid transfer protein (PLTP). HDLs, as they break down, donate phospholipids and cholesterol/cholesterol esters, which are bound by SR-B1 receptor on liver cells. LDLs are bound by LDL receptor (LDLR) on hepatocytes. ApoA1 can be reused or secreted by the liver. Cholesterol can be reused or secreted into the bile for disposal. Triangles = apoA1; diamond = apoB. CE, cholesterol esters; FC, free cholesterol; PL, phospholipids; TG, triglycerides. The figure is based, in part, on figures and data in [102] and [103].