Novel approaches to treating cardiovascular disease: lessons from Tangier disease

Atherosclerotic cardiovascular disease (CVD) remains the leading cause of morbidity and mortality in Western societies. Although cholesterol is a major CVD risk; factor, therapeutic interventions to loa er plasma cholesterol levels have had limited success in reducing coronary events. Thus, novel approaches are needed to reduce or eliminate CVD. A potential therapeutic target is a newly discovered ATP binding cassette transporter called ABCA1 a cell membrane protein that is the gateway for secretion of excess cholesterol from macrophages into the high density lipoprotein (HDL) metabolic pathway. Mutations in ABCA1 cause Tangier disease, a severe HDL deficiency syndrome characterised by accumulation of cholesterol in tissue macrophages and prevalent atherosclerosis. Studies of Tangier disease heterozygotes revealed that the relative activity of ABCA1 determines plasma HDL levels and susceptibility to CVD. Drugs that induce ABCA1 in mice increase clearance of cholesterol from tissues and inhibit intestinal absorption of dietary cholesterol. Thus, ABCA1-stimulating drugs have the potential to both mobilise cholesterol from atherosclerotic lesions and eliminate cholesterol from the body. By reducing plaque formation and rupture independently of the atherogenic factors involved, these drugs would be powerful agents fur treating CVD.