The dual nature of HDL: Anti-Inflammatory and pro-Inflammatory.

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.

A novel approach to oral apoA-I mimetic therapy.

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 significant). 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 provides a novel approach to oral apoA-I mimetic therapy.