Functionally Defective High Density Lipoprotein is Pro-Oxidant: a Deviation from Normal Atheroprotective Character

Abstract

High-density lipoprotein is a potential life saving antiatherogenic molecule. However, not all HDL is functionally similar, it can become dysfunctional and may increase atherosclerotic risk. At present, it is unknown, which structural alterations of HDL are essential accounting for its defective functionality and the precise pro-atherogenic mechanisms of action. This study is aimed at identification of the possible prevalence of dysfunctional HDL in subjects and its compositional and functional characterization in comparison to that of functional HDL. HDL was isolated from serum by ultracentrifugation and subjected to functional assays. HDL from majority of healthy subjects showed remarkable antioxidant property by inhibiting LDL oxidation. However, in those healthy subjects with systemic oxidative stress and inflammatory response as well as in those with known coronary heart disease, HDL was dysfunctional and promoted LDL oxidation. Dysfunctional HDL was truly pro-oxidant as it induced intracellular reactive oxygen species formation in cultured monocytes/macrophages. Functional deficiency in HDL did not show any association with HDL-cholesterol content. However, its characterization showed an enrichment of triglycerides, phospholipids, lipid peroxides, and diminished activity of paraoxonase-1, compared to functional HDL, which might render the particle dysfunctional and pro-oxidant.This study demonstrates the prevalence of dysfunctional HDL even among healthy subjects, despite normal HDL-C level, and in majority of subjects with known CHD, which is pro-oxidant in nature that might promote vascular inflammation and atherogenesis. The functional assay of HDL could lead to improved predictive accuracy of cardiovascular disease risk associated with circulating HDL.

Adverse effects on macrophage lipid transport and survival by high density lipoprotein from patients with coronary heart disease

“…The effect of dysfunctional HDL on macrophage cholesterol accumulation was examined at different time intervals (6,12, and 24 h).…”

“…Excess cholesterol is toxic to the cells. To examine the effect of piHDL on cytotoxicity, human macrophages were exposed to piHDL at different time intervals (6,12,16, and 24 h).The cell viability rate was quantitated by MTT assay. As shown in Figure 2a, the viability of macrophages decreased gradually in a time-dependent manner in response to piHDL.…”

“…However, all HDL are functionally not equivalent and there is much that is unknown about HDL. [6] The dysfunctional HDL has distinct composition and it showed an enrichment of triglycerides (TG), phospholipids, lipid peroxides, and depletion of paraoxonase-1 activity, compared to functional HDL from healthy subjects. [4] Several studies have shown that infection, inflammation, diabetes, and coronary artery disease (CAD) are associated with dysfunctional HDL.…”

“…[5] We have recently reported that HDL from patients with established CAD, exhibits dysfunctionality with total reduction in its antioxidant property to inhibit LDL oxidation in vitro and it also stimulates pro-oxidant effects in human monocytes. [6] The dysfunctional HDL has distinct composition and it showed an enrichment of triglycerides (TG), phospholipids, lipid peroxides, and depletion of paraoxonase-1 activity, compared to functional HDL from healthy subjects. Further characterization demonstrated an exclusive association of a protease, matrix metalloproteinase-9 with dysfunctional HDL.…”

The contribution of paraoxonase 1 and myeloperoxidase to HDL-cholesterol functionality

“…Moreover, clinical trials aimed at raising the circulating HDL-cholesterol have failed to reduce the cardiovascular outcomes [30]. The doubts concerning the protective role of HDL-C have been supported by in vitro studies which indicate that the HDL-C from patients with CVD does not have a protective action, but does stimulate inflammation and free radical synthesis [60,77]. This data suggests that HDL-C, commonly recognised as protective against atherosclerosis, in some circumstances becomes pro-atherogenic and dysfunctional [79].…”