d-4f-peptide and Coronary-Disease

Although high-density lipoprotein-cholesterol (HDL-C) levels in large epidemiological studies are inversely related to the risk of coronary heart disease (CHD), increasing the level of circulating HDL-C does not necessarily decrease the risk of CHD events, CHD deaths, or mortality. HDL can act as an anti- or a pro-inflammatory molecule, depending on the context and environment. Based on a number of recent studies, it appears that the anti- or pro-inflammatory nature of HDL may be a more sensitive indicator of the presence or absence of atherosclerosis than HDL-C levels. The HDL proteome has been suggested to be a marker, and perhaps a mediator, of CHD. Apolipoprotein A-1 (apoA-I), the major protein in HDL is a selective target for oxidation by myeloperoxidase, which results in impaired HDL function. Improving HDL function through modification of its lipid and/or protein content maybe a therapeutic target for the treatment of CHD and many inflammatory disorders. HDL/apoA-I mimetic peptides may have the ability to modify the lipid and protein content of HDL and convert dysfunctional HDL to functional HDL. This review focuses on recent studies of dysfunctional HDL in animal models and human disease, and the potential of apoA-I mimetic peptides to normalize the composition and function of lipoproteins.

Topics: Animals; Apolipoprotein A-I; Biomimetics; Coronary Disease; Disease Models, Animal; Humans; Intercellular Signaling Peptides and Proteins; Lipoproteins, HDL; Mice; Peptides

High-density lipoprotein cholesterol is a potent and independent epidemiologic risk factor and is a proved antiatherosclerotic agent in animal models of atherosclerosis, acting through the principal mechanisms of accelerating cholesterol efflux and inhibiting oxidation and inflammation. Lifestyle modification increases serum levels by 5% to 15%, whereas niacin, the drug most widely used to increase high-density lipoprotein cholesterol, increases it by 25% to 35% at the highest doses. This review examines the potent methods of increasing high-density lipoprotein and/or enhancing reverse cholesterol transport, including cholesterol ester transfer protein inhibitors, apolipoprotein A-I Milano, D4F, the dual peroxisome proliferator-activated receptor agonists, and rimonabant, that are now in clinical trials. In conclusion, these new agents, used alone or in combination with existing therapies, carry the potential to markedly reduce the incidence of new coronary disease and cardiac events in this decade.

Topics: Animals; Apolipoprotein A-I; Atherosclerosis; Cannabinoid Receptor Antagonists; Cholesterol Ester Transfer Proteins; Cholesterol, HDL; Cholesterol, LDL; Coronary Disease; Humans; Lipoproteins, HDL; Peroxisome Proliferator-Activated Receptors; Piperidines; Pyrazoles; Rimonabant; Risk Factors