The effect of phospholipid composition of reconstituted HDL on its cholesterol efflux and anti-inflammatory properties

Abstract

Infusions of cholesterol-free reconstituted HDL (rHDL) particles have been shown to rapidly reverse atherosclerosis in a wide variety of animal models and in clinical trials of acute coronary syndrome patients ( 1-5 ). While a significant emphasis has been placed on investigating the HDL protein component, i.e., ApoA-I, ApoA-I mutants, and mimetic peptides, the importance of HDL phospholipid (PL) composition has not been systematically investigated. Lipid represents 50-80% of the total HDL mass and is known to affect particle stability in vivo, cholesterol effl ux from macrophages, the ability to interact with LCAT, and cholesterol elimination ( 6-11 ). Lipid composition also largely defi nes the size, net charge, and rigidity of the rHDL particles; all are important factors in the pharmacokinetic and pharmacodynamic properties of rHDL. The investigation of the effects of lipid composition on the resulting rHDL properties in vitro and in vivo is the focus of this article. By better defi ning the lipid effect of rHDL, we hope to be able to favorably alter the potency and safety of rHDL, and ultimately advance clinical translation of these potentially life-changing nanomedicines.The PL composition of endogenous HDL contains phosphatidylcholines (PCs), SM, and small amounts of lysophosphatidylcholine (LPC), phosphatidylethanolamine, Abstract The goal of this study was to understand how the reconstituted HDL (rHDL) phospholipid (PL) composition affects its cholesterol effl ux and anti-infl ammatory properties. An ApoA-I mimetic peptide, 5A, was combined with either SM or POPC. Both lipid formulations exhibited similar in vitro cholesterol effl ux by ABCA1, but 5A-SM exhibited higher ABCG1-and SR-BI-mediated effl ux relative to 5A-POPC ( P < 0.05). Injection of both rHDLs in rats resulted in mobilization of plasma cholesterol, although the relative potency was 3-fold higher for the same doses of 5A-SM than for 5A-POPC. Formation of pre ␤ HDL was observed following incubation of rHDLs with both human and rat plasma in vitro, with 5A-SM inducing a higher extent of pre ␤ formation relative to 5A-POPC. Both rHDLs exhibited antiinfl ammatory properties, but 5A-SM showed higher inhibition of TNF-␣ , IL-6, and IL-1 ␤ release than did 5A-POPC ( P < 0.05). Both 5A-SM and 5A-POPC showed reduction in total plaque area in ApoE ؊ / ؊ mice, but only 5A-SM showed a statistically signifi cant reduction over placebo control and baseline ( P < 0.01). The type of PL used to reconstitute peptide has signifi cant infl uence on rHDL's anti-infl ammatory and anti-atherosclerosis properties.

Dysfunctional high-density lipoproteins in coronary heart disease: implications for diagnostics and therapy

“…100 rHDL containing sphingomyelin was also found to be a more potent inhibitor of cytokine release. 100 In line with this observation, the presence of coronary heart disease in post-menopausal women was inversely related to sphingomyelin in HDL. 101 The lysosphingolipid S1P is probably the most intensively studied sphingolipid of HDL.…”

Lupus high-density lipoprotein induces proinflammatory responses in macrophages by binding lectin-like oxidised low-density lipoprotein receptor 1 and failing to promote activating transcription factor 3 activity

“…Circulating HDL can bind and trap neighbouring molecules that, in turn, could affect the lipoprotein's immunogenicity. Changes in phospholipid composition can affect the anti-inflammatory capacity of HDL 27. Future analysis should explore differences in HDL lipid and protein cargo among different inflammatory conditions.…”

Synthetic high-density lipoproteins for delivery of 10-hydroxycamptothecin

“…This weight ratio of 5A to phospholipid is known to form homogeneous sHDL nanoparticles of 8-12 nm diameter. 29 The particle size and size homogeneity of sHDL made with different phospholipids were similar ( Table 1). The highest HCPT EE (71%) was achieved for SM-based sHDL, followed by DPPC-based (49%), POPC (16%), and DMPC (12%).…”

“…34 The 5A-SM has been shown to exhibit strong SR-BI-mediated efflux deemed beneficial for antiatherosclerotic properties of this sHDL. 29 Normally the antitumor activity of sHDL is observed at relatively high dosages, such as 0.1-0.2 mg/mL of 22A-sHDL, is required to generate in vitro cytotoxicity in NCI-H295R and SW13 cells 35 and 250 mg/kg of R4F-sHDL to inhibit the tumor growth in vivo. 36 The improved activity of HCPT-sHDL is unlikely to be attributed to a synergetic effect between topoisomerase I inhibition by HCPT and cholesterol efflux by sHDL based on no statistically significant improvement in cytotoxicity of the physical mixture of sHDL and HCPT.…”