Roles of Reconstituted High-Density Lipoprotein Nanoparticles in Cardiovascular Disease: A New Paradigm for Drug Discovery

Abstract

Epidemiological results revealed that there is an inverse correlation between high-density lipoprotein (HDL) cholesterol levels and risks of atherosclerotic cardiovascular disease (ASCVD). Mounting evidence supports that HDLs are atheroprotective, therefore, many therapeutic approaches have been developed to increase HDL cholesterol (HDL-C) levels. Nevertheless, HDL-raising therapies, such as cholesteryl ester transfer protein (CETP) inhibitors, failed to ameliorate cardiovascular outcomes in clinical trials, thereby casting doubt on the treatment of cardiovascular disease (CVD) by increasing HDL-C levels. Therefore, HDL-targeted interventional studies were shifted to increasing the number of HDL particles capable of promoting ATP-binding cassette transporter A1 (ABCA1)-mediated cholesterol efflux. One such approach was the development of reconstituted HDL (rHDL) particles that promote ABCA1-mediated cholesterol efflux from lipid-enriched macrophages. Here, we explore the manipulation of rHDL nanoparticles as a strategy for the treatment of CVD. In addition, we discuss technological capabilities and the challenge of relating preclinical in vivo mice research to clinical studies. Finally, by drawing lessons from developing rHDL nanoparticles, we also incorporate the viabilities and advantages of the development of a molecular imaging probe with HDL nanoparticles when applied to ASCVD, as well as gaps in technology and knowledge required for putting the HDL-targeted therapeutics into full gear.

Reactive Dicarbonyl Scavenging Effectively Reduces MPO-Mediated Oxidation of HDL and Restores PON1 Activity

“…Furthermore, our recent studies showed that FH versus control HDL contain increased isolevuglandins, which are highly reactive γ-ketoaldehydes [14], and direct modification of HDL with isolevuglandins caused a proinflammatory response to LPS. In addition to oxidation products, other factors such as LCAT, CETP, microRNAs, apoL1, and sphingosine-1-phosphate could impact the anti-inflammatory function of FH-HDL [48][49][50].…”

Cardiovascular, Metabolic and Inflammatory Changes after Ovariectomy and Estradiol Substitution in Hereditary Hypertriglyceridemic Rats

“…In addition, concentration of HDL cholesterol increased significantly after ovariectomy and increased even further if ovariectomy was followed by estradiol substitution. It should be noted, that neither in human plasma serum/plasma concentration of HDL cholesterol exactly reflect structure or mechanisms of the real metabolic activity of HDL particles [ 39 ]. In addition, in rodents HDL cholesterol could play different roles than in humans [ 40 ].…”

Pharmacological Therapeutics Targeting RNA-Dependent RNA Polymerase, Proteinase and Spike Protein: From Mechanistic Studies to Clinical Trials for COVID-19

“…Some traditional Chinese medicines such as Polygonum cuspidatum that may consist of components with efficacy against COVID-19 have been examined in clinical trials [105]. The pro-inflammatory metabolites of arachidonic acid (AA) and eicosapentaenoic acid (EPA) such as leukotrienes and thromboxanes promote inflammation, whereas lipoxins, resolvins, protectins and maresins derived from AA, EPA and DHA facilitate wound healing, promote phagocytosis of macrophages and other immunocytes and decrease microbial load [106]. It is implicated that these unsaturated fatty acids and pro-inflammatory metabolites may serve as endogenous anti-viral compounds.…”