High density lipoprotein (HDL), its main protein, apolipoprotein A-I (apoA-I), and mimetics of apoA-I have been shown in a number of laboratories to reduce infl ammation in animal models of disease ( 1-5 ). The apoA-I mimetic peptide 4F showed great promise in a variety of mouse models of disease ( 5 ) leading to a phase I/II study in humans with a high risk of cardiovascular disease ( 6 ). In this study the 4F peptide synthesized from all D-amino acids (D-4F) was administered orally at doses that ranged from 0.43 to 7.14 mg/kg. The resulting plasma peptide levels were low [maximal plasma concentration (Cmax) 15.9 ± 6.5 ng/ml]. Despite these very low plasma levels, doses of 4.3 and 7.14 mg/kg signifi cantly improved the HDL infl ammatory index (HII), which is a measure of the ability of a test HDL to inhibit LDL-induced monocyte chemoattractant protein-1 (MCP-1) production by cultured human artery wall cells; doses of 0.43 and 1.43 mg/kg were not effective ( 6 ). A second clinical trial focused on achieving high plasma peptide levels using low doses (0.042-1.43 mg/kg) of the 4F peptide synthesized from all L-amino acids (L-4F) delivered by intravenous (IV) or subcutaneous (SQ) administration ( 7 ). Very high plasma levels were in fact achieved (e.g., Cmax 3,255 ± 630 ng/ml in the IV study), but there was no improvement in HII ( 7 ). To resolve this paradox, new studies were conducted in mice that led to the surprising discovery that the major site of action for the peptide may be in the intestine, even when the peptide is administered SQ ( 8 ). Moreover, the dose administered, not the plasma level, was the major Abstract Transgenic tomato plants were constructed with an empty vector (EV) or a vector expressing an apoA-I mimetic peptide , 6F. EV or 6F tomatoes were harvested, lyophilized, ground into powder, added to Western diet (WD) at 2.2% by weight, and fed to LDL receptor-null (LDLR ؊ / ؊ ) mice at 45 mg/kg/day 6F. After 13 weeks, the percent of the aorta with lesions was 4.1 ± 4%, 3.3 ± 2.4%, and 1.9 ± 1.4% for WD, WD + EV, and WD + 6F, respectively (WD + 6F vs. WD, P = 0.0134; WD + 6F vs. WD + EV, P = 0.0386; WD + EV vs. WD, not signifi cant). While body weight did not differ, plasma serum amyloid A (SAA), total cholesterol, triglycerides, and lysophosphatidic acid (LPA) levels were less in WD + 6F mice; P < 0.0295. HDL cholesterol and paroxonase-1 activity (PON) were higher in WD + 6F mice ( P = 0.0055 and P = 0.0254, respectively), but not in WD + EV mice. Plasma SAA, total cholesterol, triglycerides, LPA, and 15-hydroxyeicosatetraenoic acid (HETE) levels positively correlated with lesions ( P < 0.0001); HDL cholesterol and PON were inversely correlated ( P < 0.0001). After feeding WD + 6F: i ) intact 6F was detected in small intestine (but not in plasma); ii ) small intestine LPA was decreased compared with WD + EV ( P < 0.0469); and iii ) small intestine LPA 18:2 positively correlated with the percent of the aorta with lesions ( P < 0.0179). These data suggest that 6F acts in the small intestine and pr...

High density lipoprotein (HDL) has long been considered a protective factor against the development of coronary heart disease. Two important roles of HDL include reverse cholesterol transport (RCT) and the modulation of inflammation. The main protein component of HDL; apolipoprotein A-I (apo A-I) is primarily responsible for RCT. Apo A-I can be damaged by oxidative mechanisms, which reduce the protein's ability to promote RCT. In disease states such as diabetes, associated with a chronic acute-phase response, HDL has been found to be dysfunctional and pro-inflammatory. HDL cholesterol levels do not predict composition and/or function and therefore it is important to evaluate the quality and not just the quantity of HDL cholesterol when considering the risk of cardiovascular events. In clinical practice, there are currently no widely available tests for measuring the composition, functionality, and inflammatory properties of HDL. Small peptides that mimic some of the properties of apo A-I have been shown in pre-clinical models to improve HDL function and reduce atherosclerosis without altering HDL cholesterol levels. Clinical trials using HDL and HDL mimetics as therapeutic agents are currently underway. Results in animal studies and early clinical trials will be reviewed.