Defense mechanisms responsible for maintaining endothelial and vessel wall homeostasis, including: 1) endothelial progenitor cells; 2) angiogenesis and plaque neovascularization; and 3) reverse cholesterol transport and plaque regression. LDL = low-density lipoprotein; MMP = matrix metalloproteinase; TF = tissue factor. Modified, with permission, from Fuster et al. (10).

Cumulative event-free survival in an analysis of death from cardiovascular causes at 12 months according to levels of circulating CD34⁺ KDR⁺ endothelial progenitor cells at the time of enrollment. Reprinted, with permission, from Werner et al. (24).

The haptoglobin (Hp)-1 and -2 genotypes play opposite roles in macrophage function after plaque hemorrhage. In individuals with the Hp-1 genotype, a redox-inactive, hemoglobin (Hb)–Hp-1 complex is generated that binds to the macrophage CD163 receptor to induce the secretion of anti-inflammatory cytokines such as interleukin-10 (IL-10). Conversely, after plaque hemorrhage in individuals with the Hp-2 genotype, a redox-active Hb–Hp-2 complex is generated that produces reactive oxygen species (ROS) and induces macrophages to secrete proinflammatory cytokines by both CD163-dependent and -independent pathways, as shown. NF = nuclear transcription factor. Reprinted, with permission, from Moreno et al. (48).

Hemoglobin (Hb) released intravascularly from red blood cells (RBCs) is rapidly bound by haptoglobin (Hp) protein to form an Hp-Hb complex. In Hp 2-2 diabetic individuals, the complex is cleared by the scavenger receptor CD163 more slowly than in Hp 1-1 diabetic individuals. The Hp-Hb complex can bind to apolipoprotein (Apo)A-I in high-density lipoprotein (HDL), with increased binding of Hp 2-2-Hb occurring due to its increased avidity for HDL and its increased plasma concentration. The Hp 2-2–Hb, but not the Hp 1-1–Hb complex, when bound to HDL can produce reactive oxygen species, which can oxidize protein (i.e., ApoA-I; GPx-glutatione peroxidase; lecithin cholesterol acyltransferase [LCAT]) and lipid components (cholesterol [chol]) of HDL and render the HDL dysfunctional (due to decreased reversed cholesterol transport [RCT] and antioxidant activity), proatherogenic, and prothrombotic. DM = diabetes mellitus. Reprinted, with permission, from Asleh et al. (71).

There are 3 major pathways by which HDL may mediate cholesterol efflux from cholesterol-loaded macrophages (left). The first pathway, passive diffusion, involves exchange of free cholesterol (FC) between mature spherical -HDL and the cellular membrane. Net cholesterol efflux occurs after the conversion of FC to cholesterol ester (CE) by LCAT. In the SR-BI pathway, free cholesterol is transported to mature spherical -HDL. The third pathway involves the ABCA1 transporter. In the ABCA1 transporter pathway, the preferred acceptor of cellular cholesterol is poorly lipidated ApoA-I, which binds to the ABCA1 transporter and facilitates the efflux of cellular cholesterol from the late endocytic compartment, thereby decreasing the cholesterol content of the cell. The efflux of cholesterol and phospholipids (PL) from macrophages and other peripheral tissues results in the formation of preβ-HDL, which is ultimately converted to mature spherical -HDL after the esterification of FC to CE by LCAT. (Right) Both the SR-BI and ABCA1 transporter pathways are regulated by the oxycholesterol content of the cell. Excess cellular cholesterol is converted, at least in part, to 27-hydroxycholesterol by 27-hydroxylase. The 27-hydroxycholesterol binds to the ligand-stimulated transcription factor LXR, which, after dimerization with RXR, binds to the LXRE promoter element and increases the expression of SR-BI and the ABCA1 transporter genes. Thus, both mature and preβ-HDL facilitate the efflux of cellular cholesterol and participate in reverse cholesterol transport to the liver. Abbreviations as in Figure 4. Reprinted, with permission, from Brewer et al. (85).