HDL and Atherothrombotic Vascular Disease

Abstract

High-density lipoproteins (HDLs) exert many beneficial effects which may help to protect against the development or progression of atherosclerosis or even facilitate lesion regression. These activities include promoting cellular cholesterol efflux, protecting low-density lipoproteins (LDLs) from modification, preserving endothelial function, as well as anti-inflammatory and antithrombotic effects. However, questions remain about the relative importance of these activities for atheroprotection. Furthermore, the many molecules (both lipids and proteins) associated with HDLs exert both distinct and overlapping activities, which may be compromised by inflammatory conditions, resulting in either loss of function or even gain of dysfunction. This complexity of HDL functionality has so far precluded elucidation of distinct structure-function relationships for HDL or its components. A better understanding of HDL metabolism and structure-function relationships is therefore crucial to exploit HDLs and its associated components and cellular pathways as potential targets for anti-atherosclerotic therapies and diagnostic markers.

Dysfunctional high-density lipoproteins in coronary heart disease: implications for diagnostics and therapy

“…5,13 The classical anti-antherogenic role of HDL in cardiovascular disease is its potential to drive cholesterol export from macrophage foam cells and subsequent transport towards the liver for excretion into bile and feces, i.e. reverse cholesterol transport.…”

“…Although present at very low concentrations lipid-free apoA-I, which because of its electrophoretic mobility is termed prebeta1-HDL, is a very potent inducer of active cholesterol efflux by ABCA1. 4,5,[13][14][15] Both ABCA1 and ABCG1 are integrated into both positive feed-forward and negative feed-back regulation loops of cellular cholesterol homeostasis involving both transcriptional regulation by oxysterol-activated nuclear liver X receptors and post-transcriptional regulation by several miRNAs. Thus, cholesterol efflux is determined by the extracellular concentration and composition of HDL particles as well as by the activity of ABC transporters.…”

“…Thus, cholesterol efflux is determined by the extracellular concentration and composition of HDL particles as well as by the activity of ABC transporters. 4,5,[13][14][15] By modulating cellular cholesterol homeostasis, both apoA-I and HDL indirectly regulate survival and functions of several cell types ( Figure 1). 4,5 Numerous other potential atheroprotective functions of HDL have been described and the list is still growing.…”

Smooth Muscle Cell Foam Cell Formation, Apolipoproteins, and ABCA1 in Intracranial Aneurysms: Implications for Lipid Accumulation as a Promoter of Aneurysm Wall Rupture

“…Lipoproteins may enter intact vascular wall with a normal endothelial barrier function via endothelial cell transcytosis (22). Importantly, endothelial dysfunction increases lipoprotein influx via endothelial cell junctions, and more severe damage of endothelium may allow unrestricted entry of lipoproteins into the vessel wall (22).…”

“…Therefore, the apoA-I-dependent induction of cholesterol efflux from intracellular stores in foam cells macrophage origin or SMC origin, that is, the initial steps occurring in the arterial wall, are critical for the antiatherosclerotic activity of HDL (21). Apolipoprotein E (apoE) (22), a structural component of apoB-100-containing lipoproteins, can be present also in a small fraction of HDL particles and, by interacting with arterial proteoglycans, it may cause HDL retention in the vessel wall (23).…”