The Role of High-Density Lipoprotein Cholesterol in the Prevention and Possible Treatment of Cardiovascular Diseases

Abstract

Despite significant progress in the management of atherosclerosis and its resultant complications, cardiovascular disease remains the principal cause of death in the world. The National Cholesterol Education Project Adult Treatment Panel III (NCEP ATP III) recognizes low levels of high-density lipoprotein cholesterol (HDL) as a risk factor for coronary heart disease (CHD) and high levels of HDL as a risk-reducing factor; however, the elevation of HDL as a specific therapeutic target for the prevention and treatment of CHD has yet to be accepted on the same level as low-density lipoprotein (LDL)-reducing therapies. Current HDL elevators including nicotinic acid, fibric acid derivatives, peroxisome proliferator activated receptor (PPAR) agonists and statins also affect other lipid constituents which make interpretation of the clinical trials of these drugs difficult in teasing out the independent effect of HDL elevation. Ample laboratory investigation suggests that HDL elevation would reduce atherosclerotic burden through multiple independent mechanisms. In this review, we explore HDL biology, its potential mechanisms in the treatment of atherosclerotic disease, and promising new drugs with HDL-raising activity.

Shedding Light on High-Density Lipoprotein Cholesterol

“…Although much of the antiatherosclerotic properties of HDL-C is considered to be mediated by reverse cholesterol transport (RCT), a process in which excess cholesterol in cells and, particularly, atherosclerotic plaque is removed, HDL-C has other beneficial effects, including reducing endothelial dysfunction, as well as antiinflammatory, antioxidant, and antithrombotic effects (13,14). Despite these potential theoretical benefits and the substantial epidemiologic and limited pharmacologic data that would support clinical event reduction with HDL-C raising interventions, several trials with fibrates (15)(16)(17), estrogens (18,19), and, particularly, cholesterol ester transport protein (CETP) inhibition with torcetrapib (20) have demonstrated neutral effects or even harm related to HDL-C-elevating interventions.…”

“…Despite substantial enthusiasm directed toward CETP inhibition and the first agent in its class, torcetrapib, the failure of this agent to reduce CHD events and possibly cause harm were partly predictable (4,13). Although a possible contributing factor to torcetrapib's downfall was that it increased blood pressure in some patients, its major failure was likely due to producing HDL-C elevation without RCT augmentation (4,20).…”

TP53 codon 72 polymorphism as a risk factor for cardiovascular disease in a Brazilian population

“…Lower levels of HDL lipoprotein have been considered to be an independent risk factor for cardiovascular disease and type II diabetes (35). Moreover, modification of low-density lipoprotein by endothelial cells has been associated with lipid peroxidation and with degradation of low-density lipoprotein phospholipids (36).…”

Genesis and Dynamics of Atherosclerotic Lesions: Implications for Early Detection

“…Through their metabolic maturation, HDLs interact with the ABCA1 receptor in the macrophage surface increasing their lipid content by taking phospholipids and cholesterol from macrophages becoming mature HDL. The cholesterol of the HDLs is transported to the liver, via the scavenger receptor class B, type I (SR-BI), for further metabolization and excretion to the intestines in the form of bile acids and cholesterol, completing the process of RCT [8, 9]. In mammals, the liver is the only organ capable of synthesizing and metabolizing cholesterol.…”