Abstract
Cardiovascular disease (CVD), the leading cause of mortality worldwide is primarily caused by atherosclerosis, which is promoted by the accumulation of low-density lipoproteins into the intima of large arteries. Multiple nanoparticles mimicking natural HDL (rHDL) have been designed to remove cholesterol excess in CVD therapy. The goal of this investigation was to assess the cholesterol efflux efficiency of rHDLs with different lipid compositions, mimicking different maturation stages of high-density lipoproteins (HDLs) occurring in vivo. Methods: the cholesterol efflux activity of soybean PC (Soy-PC), 1,2-dipalmitoyl-sn-glycero-3-phosphocholine (DPPC), DPPC:Chol:1-palmitoyl-2-hydroxy-sn-glycero-3-phosphocholine (LysoPC) and DPPC:18:2 cholesteryl ester (CE):LysoPC rHDLs was determined in several cell models to investigate the contribution of lipid composition to the effectiveness of cholesterol removal. Results: DPPC rHDLs are the most efficient particles, inducing cholesterol efflux in all cellular models and in all conditions the effect was potentiated when the ABCA1 transporter was upregulated. Conclusions: DPPC rHDLs, which resemble nascent HDL, are the most effective particles in inducing cholesterol efflux due to the higher physical binding affinity of cholesterol to the saturated long-chain-length phospholipids and the favored cholesterol transfer from a highly positively curved bilayer, to an accepting planar bilayer such as DPPC rHDLs. The physicochemical characteristics of rHDLs should be taken into consideration to design more efficient nanoparticles to promote cholesterol efflux.
Highlights
Cardiovascular disease (CVD), the leading cause of mortality in industrially developed countries [1], is primarily caused by atherosclerosis, characterized by an abnormal lipid and inflammatory cell accumulation in the intima, the subendothelial layer of large arteries [2].Atherosclerosis is associated with atheroma plaque formation and reduction in the vascular diameter, increasing the incidence of cardiovascular events [3]
When applying the reconstituted HDL (rHDL) samples, the aggregates were present in the void volume of the size exclusion column at 7–9 mL, and a rHDL homogenous peak was centered at 11–13 mL, preceding free apolipoprotein A-I (apoA-I) at 15 mL (Figure 1A)
Our results indicate that DPPC rHDLs, which resemble nascent high-density lipoproteins (HDLs), are the most effective particles inducing cholesterol efflux in all the cellular models used
Summary
Cardiovascular disease (CVD), the leading cause of mortality in industrially developed countries [1], is primarily caused by atherosclerosis, characterized by an abnormal lipid and inflammatory cell accumulation in the intima, the subendothelial layer of large arteries [2].Atherosclerosis is associated with atheroma plaque formation and reduction in the vascular diameter, increasing the incidence of cardiovascular events [3]. Biomedicines 2020, 8, 373 by selective entrapment of low-density lipoproteins (LDL) in the extracellular arterial intima, and is mediated by the interaction of specific positively charged amino acyl residues of apoB100 with arterial proteoglycans [4,5,6] This interaction constitutes the central biochemical and pathogenic process because the proteoglycans initiate lipoprotein degradation with the production of bioactive, lipid products that trigger an inflammatory response which leads to aterosclerosis [7]. Removal of cholesterol excess from peripheral tissues is carried out by apolipoprotein A-I (apoA-I) containing high-density lipoproteins (HDL), through a mechanism known as reverse cholesterol transport (RCT) [12] This process is facilitated by apoA-I interaction with members of the ATP-binding cassette transporters superfamily such as ABCA1, a cholesterol efflux mediator present in various cell types such as hepatocytes, enterocytes, and macrophages [13,14]. The ABCG1 transporter mediates cholesterol transport to the assembled HDL [21,22], but not to lipid-free apoA-I [21,23]
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