Dysfunctional HDL: From Structure-Function-Relationships to Biomarkers

Abstract

Reduced plasma levels of HDL-C are associated with an increased risk of CAD and myocardial infarction, as shown in various prospective population studies. However, recent clinical trials on lipidmodifying drugs that increase plasma levels of HDL-C have not shown significant clinical benefit. Notably, in some recent clinical studies, there is no clear association of higher HDL-C levels with a reduced risk of cardiovascular events observed in patients with existing CAD. These observations have prompted researchers to shift from a cholesterol-centric view of HDL towards assessing the function and composition of HDL particles. Of importance, experimental and translational studies have further demonstrated various potential antiatherogenic effects of HDL. HDL has been proposed to promote macrophage reverse cholesterol transport and to protect endothelial cell functions by prevention of oxidation of LDL and its adverse endothelial effects. Furthermore, HDL from healthy subjects can directly stimulate endothelial cell production of nitric oxide and exert anti-inflammatory and antiapoptotic effects. Of note, increasing evidence suggests that the vascular effects of HDL can be highly heterogeneous and HDL may lose important anti-atherosclerotic properties and turn dysfunctional in patients with chronic inflammatory disorders. A greater understanding of mechanisms of action of HDL and its altered vascular effects is therefore critical within the context of HDL-targeted therapies.

Statin action enriches HDL3 in polyunsaturated phospholipids and plasmalogens and reduces LDL-derived phospholipid hydroperoxides in atherogenic mixed dyslipidemia

“…Indeed, both absolute levels and profiles of total PC-P + PE-P(20:4) and PC-P + PE-P(22:6) at D0 and at D180 in native LDL, HDL2, and HDL3 obtained by LC/MS closely resembled those quantitated as total plasmalogen by HPLC protects against the action of a wide spectrum of reactive oxygen species (ROS) and attenuates LDL oxidation in part by removal of seeding LOOH species (21,22,24,26,27,32,34,51). Central to HDL-mediated antioxidative activity is the direct reduction of LOOHs by methionine residues of apoAI and apoAII, with conversion to residuespecific methionine sulfoxides (apoAI + 16, apoAI + 32, and apoAII + 16) (21,(30)(31)(32).…”

“…Equally, however, evidence is emerging that HDL-associated plasmalogens, PLs containing a vinylether bond of high oxidative susceptibility, are implicated in this potentially antiatherogenic process (26,(33)(34)(35). Indeed, it is of immediate relevance that the oxidative products of plasmalogens do not propagate lipid peroxidation, thereby attenuating formation of proatherogenic secondary oxidation products such as aldehydes (33,35,36).…”

“…By contrast, it is now established that HDL particles display defective biological activities across a wide range of dyslipidemic states associated with premature atherosclerotic vascular disease, and that such dysfunction is intimately linked to alterations in their lipidomic and proteomic profiles (22)(23)(24)(25)(26)(27). With respect to the lipidome, alterations in content of both neutral core [triacylglycerols and CEs] and electrostatically charged surface lipids [sphingolipids and phospholipids (PLs)] are implicated in HDL dysfunction in dyslipidemia (22)(23)(24)(25)(26)(27). To what degree then might statinmediated modulation of HDL metabolism and particle composition impact the HDL lipidome, and might such modulation contribute to potential statin-mediated normalization of defective HDL function in dyslipidemic states?…”

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

“…16 Since then, a broad spectrum of dysfunctions of HDL in patients with cardiovascular diseases has been described, including a reduced cholesterol efflux capacity from macrophages and other cells, impaired anti-oxidative effects, a reduced ability to inhibit adhesion molecule expression on endothelial cells, a lack of the normal ability to stimulate endothelial nitric oxide bioavailability as well as diminished activities to promote endothelial cell survival. 5,39 There are several examples of dysfunction where HDL was not only characterized by loss or reduction of normal functionality but by the gain of atypical functions. For example, HDL of patients with CAD or chronic kidney disease (CKD) was found to inhibit rather than stimulate nitric oxide production because it gained the ability to interact with the lectin-like oxidized LDL receptor LOX-1 and the toll-like receptors TLR2 and TLR4, respectively.…”

Percutaneous Coronary Intervention Rates and Associated Independent Predictors for Progression of Nontarget Lesions in Patients With Diabetes Mellitus After Drug-Eluting Stent Implantation

“…Recent investigations suggest that HDL-C may lose its antiatherosclerotic properties and turn dysfunctional in patients with chronic inflammatory disorder. 31 Therefore, dysfunctional HDL-C may be another therapeutic target to reduce residual risk. 32 The present study confirmed that insulin use at the time of baseline PCI was a significant independent predictor of nontarget lesions PCI in diabetic patients after DES implantation.…”