HDL Function and Atherosclerosis: Reactive Dicarbonyls as Promising Targets of Therapy

by Selleckchem | Oct 03 2023

Epidemiologic studies detected an inverse relationship between HDL (high-density lipoprotein) cholesterol (HDL-C) levels and atherosclerotic cardiovascular disease (ASCVD), identifying HDL-C as a major risk factor for ASCVD and suggesting atheroprotective functions of HDL. However, the role of HDL-C as a mediator of risk for ASCVD has been called into question by the failure of HDL-C-raising drugs to reduce cardiovascular events in clinical trials. Progress in understanding the heterogeneous nature of HDL particles in terms of their protein, lipid, and small RNA composition has contributed to the realization that HDL-C levels do not necessarily reflect HDL function. The most examined atheroprotective function of HDL is reverse cholesterol transport, whereby HDL removes cholesterol from plaque macrophage foam cells and delivers it to the liver for processing and excretion into bile. Indeed, in several studies, HDL has shown inverse associations between HDL cholesterol efflux capacity and ASCVD in humans. Inflammation plays a key role in the pathogenesis of atherosclerosis and vulnerable plaque formation, and a fundamental function of HDL is suppression of inflammatory signaling in macrophages and other cells. Oxidation is also a critical process to ASCVD in promoting atherogenic oxidative modifications of LDL (low-density lipoprotein) and cellular inflammation. HDL and its proteins including apoAI (apolipoprotein AI) and PON1 (paraoxonase 1) prevent cellular oxidative stress and LDL modifications. Importantly, HDL in humans with ASCVD is oxidatively modified rendering HDL dysfunctional and proinflammatory. Modification of HDL with reactive carbonyl species, such as malondialdehyde and isolevuglandins, dramatically impairs the antiatherogenic functions of HDL. Importantly, treatment of murine models of atherosclerosis with scavengers of reactive dicarbonyls improves HDL function and reduces systemic inflammation, atherosclerosis development, and features of plaque instability. Here, we discuss the HDL antiatherogenic functions in relation to oxidative modifications and the potential of reactive dicarbonyl scavengers as a therapeutic approach for ASCVD.

Comments:

The paragraph you provided highlights the evolving understanding of high-density lipoprotein (HDL) and its role in atherosclerotic cardiovascular disease (ASCVD). While early epidemiological studies suggested that higher levels of HDL cholesterol (HDL-C) were associated with a reduced risk of ASCVD, clinical trials using drugs to raise HDL-C levels did not show a significant reduction in cardiovascular events. This has led researchers to question the direct role of HDL-C in ASCVD.

Further research has revealed that HDL is a complex particle with diverse functions beyond its cholesterol content. One of the most studied functions of HDL is reverse cholesterol transport, where it removes cholesterol from plaque macrophage foam cells and transports it to the liver for processing and excretion. However, HDL's protective effects against ASCVD are not solely dependent on its cholesterol transport capacity.

Inflammation is a key factor in the development of atherosclerosis and vulnerable plaque formation. HDL has been found to suppress inflammatory signaling in macrophages and other cells, thus playing a role in reducing inflammation. Additionally, oxidation is a critical process in ASCVD, promoting the modification of low-density lipoprotein (LDL) and cellular inflammation. HDL and its proteins, such as apolipoprotein AI (apoAI) and paraoxonase 1 (PON1), help prevent cellular oxidative stress and protect against LDL modifications.

However, in individuals with ASCVD, HDL can undergo oxidative modifications, rendering it dysfunctional and proinflammatory. Reactive carbonyl species, including malondialdehyde and isolevuglandins, can impair the antiatherogenic functions of HDL. Treating animal models of atherosclerosis with scavengers of these reactive dicarbonyls has shown improvements in HDL function, reduced systemic inflammation, and atherosclerosis development.

Based on these findings, researchers suggest that targeting reactive dicarbonyls could be a potential therapeutic approach for ASCVD. By improving HDL function and reducing oxidative modifications, it may be possible to enhance HDL's antiatherogenic properties and mitigate the development and progression of atherosclerosis.

It's important to note that while this paragraph provides an overview of the current understanding, research in the field of HDL and ASCVD is ongoing, and further studies are needed to fully elucidate the complex interactions and potential therapeutic strategies related to HDL function in cardiovascular disease.