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

Abstract

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.

Sex Differences Define the Vulnerability to Atherosclerosis

“…Inflammatory plaque cells release factors that attract extra immune cells and suppress their excretion, thus leading to a chronic inflammatory condition and plaque development. 8,9 Bigger plaques (stenosis >70%) that block the bloodstream eventually cause symptoms such as angina or lameness, which become chronic. Nevertheless, inflammatory plaque cells also secrete matrix metalloproteinases capable of destroying the fibrous membrane and ultimately stimulate plaque rupture, acute ischemia, and thrombosis, which are well-known as the key reason for most MIs and strokes.…”

Contrasting the relationship of serum uric acid/albumin ratio on quantitative flow ratio with other multiple composite parameters in patients with suspected coronary artery disease

“…High-density lipoprotein plays a crucial role in inhibiting inflammatory signaling within macrophages and other cells. However, in patients, oxidative modifications can impair the functionality of high-density lipoprotein, leading to a pro-inflammatory state [ 28 ]. In line with these previous findings, our study demonstrated a significant correlation between MHR and QFR ≤ 0.80, indicating its potential as a relevant marker.…”

Identifying the natural products in the treatment of atherosclerosis by increasing HDL-C level based on bioinformatics analysis, molecular docking, and in vitro experiment

“…HDL-C is considered the “good” cholesterol. Pharmacoepidemiological studies have shown that HDL-C levels are inversely associated with the incidence of CVD [ 7 , 46 ]. For a long time, the prevention and treatment of AS by increasing HDL-C has been considered to have broad prospects.…”

“…Many epidemiological studies have identified an inverse correlation between HDL levels and AS [ 7 , 8 ]. HDL is protective because it removes excess cholesterol from surrounding tissues by reverse cholesterol transport (RCT) and transporting it to the liver for bile excretion [ 9 ].…”