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. 2024 Aug 6:11:rbae089.
doi: 10.1093/rb/rbae089. eCollection 2024.

Therapeutic biomaterials with liver X receptor agonists based on the horizon of material biology to regulate atherosclerotic plaque regression in situ for devices surface engineering

Sainan Liu  1 , Jinquan Huang  1 , Jiayan Luo  1 , Qihao Bian  1 , Yajun Weng  2 , Li Li  3 , Junying Chen  1
Affiliations

Therapeutic biomaterials with liver X receptor agonists based on the horizon of material biology to regulate atherosclerotic plaque regression in situ for devices surface engineering

Sainan Liu et al. Regen Biomater. .

Abstract

Percutaneous coronary interventional is the main treatment for coronary atherosclerosis. At present, most studies focus on blood components and smooth muscle cells to achieve anticoagulation or anti-proliferation effects, while the mediated effects of materials on macrophages are also the focus of attention. Macrophage foam cells loaded with elevated cholesterol is a prominent feature of atherosclerotic plaque. Activation of liver X receptor (LXR) to regulate cholesterol efflux and efferocytosis and reduce the number of macrophage foam cells in plaque is feasible for the regression of atherosclerosis. However, cholesterol efflux promotion remains confined to targeted therapies. Herein, LXR agonists (GW3965) were introduced on the surface of the material and delivered in situ to atherogenic macrophages to improve drug utilization for anti-atherogenic therapy and plaque regression. LXR agonists act as plaque inhibition mediated by multichannel regulation macrophages, including lipid metabolism (ABCA1, ABCG1 and low-density lipoprotein receptor), macrophage migration (CCR7) and efferocytosis (MerTK). Material loaded with LXR agonists significantly reduced plaque burden in atherosclerotic model rats, most importantly, it did not cause hepatotoxicity and adverse reactions such as restenosis and thrombosis after material implantation. Both in vivo and in vitro evaluations confirmed its anti-atherosclerotic capability and safety. Overall, multi-functional LXR agonist-loaded materials with pathological microenvironment regulation effect are expected to be promising candidates for anti-atherosclerosis and have potential applications in cardiovascular devices surface engineering.

Keywords: LXR agonists; atherosclerosis; devices surface engineering; macrophage; material-biology; pathological microenvironment-regulation; therapeutic biomaterials.

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Figures

None
Graphical abstract
Figure 1.
Figure 1.
Design of surface modification materials for regulating macrophage function and intervening in the development of atherosclerosis. Schematic illustration of (A) the construction of the modified material loaded with liver X receptor agonist and (B) the brief treatment diagram for atherosclerosis.
Figure 2.
Figure 2.
Characterization of materials. (A) FTIR spectrum. The survey scan (B) and high-resolution scan of fluorine (C) of XPS. (D) Amine density and GW3965 density (E) on the material surface. (F) GW3965 cumulative release behavior of material at different time points. (G) SEM images of different samples (mean±SD, N = 3, *P ˂ 0.05, **P ˂ 0.01, ***P ˂ 0.001 and ****P ˂ 0.0001).
Figure 3.
Figure 3.
In vitro establishment of foam cell model. (A) Intracellular lipid staining under bright field and (B) intracellular dye concentration. (C) Fluorescent images of Calcein-PI staining of live and dead cells and (D) cell viability. (mean±SD, N = 3, ***P ˂ 0.001, ****P ˂ 0.0001).
Figure 4.
Figure 4.
Cytocompatibility of materials. (A, D) Fluorescence images of MA and foam cells. (B, E) CCK-8 results and (C, F) number of cells adhesion of two types of cells. (mean±SD, N ≥ 3, *P ˂ 0.05, **P ˂ 0.01, ***P ˂ 0.001).
Figure 5.
Figure 5.
Effect of different materials on macrophage polarization in vitro. (A, B) FCM analysis of the proportion of (A) M1 macrophages (labeled with CD86+) and (B) M2 macrophages (labeled with CD206+). Percentages of (C) CD86+ and (D) CD206+ cells. (E) The ratio of M1 to M2 (mean±SD, N = 3, *P ˂ 0.05, **P ˂ 0.01).
Figure 6.
Figure 6.
Characterization of intracellular inflammatory factors and ROS level after incubation with different materials. Cytokines content of (A) TNF-α and (B) IL-10 tested by ELISA. (C) Fluorescence images of ROS labeled by DHE and (D) activity of SOD (mean±SD, N = 3, *P ˂ 0.05, **P ˂ 0.01).
Figure 7.
Figure 7.
Effects of different materials on intracellular lipids. (A) Fluorescence images of dil-oxLDL and (B) comparison of mean fluorescence intensities. (C) Presentation of intracellular cholesterol efflux by different samples. (D–F) Intracellular content of TC, FC and oxLDL in macrophages, foam cells and cells treated with different samples (mean±SD, N ≥ 3, *P ˂ 0.05, **P ˂ 0.01, ***P ˂ 0.001 and ****P ˂ 0.0001).
Figure 8.
Figure 8.
Effects of different materials on phagocytosis. (A) Fluorescence images of microspheres incubated with CellTracker Red CMTPX-labeled foam cells on the sample. (B) Quantification of phagocytic function of foam cells treated with different samples (mean±SD, N ≥ 3, *P ˂ 0.05, **P ˂ 0.01, ***P ˂ 0.001).
Figure 9.
Figure 9.
Hemocompatibility of materials. (A) SEM images and (B) number of platelet adhesion on samples. (C) Hemolysis ratio of different samples. (D) Digital pictures and (E) absorbance values of the in vitro dynamic coagulation assay for different samples. (F) BCI statistical graph. (G) Illustration of ex vivo model. (H) Cross-sectional images of catheters with samples and photographs of the sample after unfolding and SEM images of material surfaces after dynamic blood circulation for 30 min (mean±SD, N ≥ 3, ***P ˂ 0.001, ****P ˂ 0.0001).
Figure 10.
Figure 10.
Comprehensive evaluation of in vitro experiments for each sample.
Figure 11.
Figure 11.
Changes of mRNA expression of ABCA1, ABCG1, LDLR, MerTK, CCR7 in macrophages after PG300 treatment (mean±SD, N = 3).
Figure 12.
Figure 12.
In vivo safety assessment. (A) H&E and Masson staining and immunofluorescence staining images of SMCs (labeled by α-SMA) and MA (labeled by CD68) of the sample after implantation in the rat abdominal aorta for 30 days (*: sample implantation site, #: intravascular lumen). Statistics of (B) neointimal thickness and (C) neointimal area at implant site. Percentage of (D) collagen, (E) SMCs and (F) macrophage in neointima (mean±SD, N ≥ 3, *P ˂ 0.05, **P ˂ 0.01, ***P ˂ 0.001, ****P ˂ 0.0001).
Figure 13.
Figure 13.
Establishment of rat model of atherosclerosis. (A) Summary of the process of modeling and subsequent sample implantation in atherosclerotic rats. (B) H&E staining of normal, after injury and high fat feeding for 5- and 7-week rat abdominal aorta. (C) Aorta gross oil red staining of two random rats after modeling for 7 weeks and (D) blood lipid testing (mean±SD, N ≥ 3, *P ˂ 0.05, **P ˂ 0.01, ***P ˂ 0.001, ****P ˂ 0.0001).
Figure 14.
Figure 14.
Detection of GW3965-modified material in liver and serum lipid. After treatment, liver and serum samples were collected and analyzed as follows: (A) Liver photographs. (B) H&E staining and (C) Oil red O staining of liver. (D) TG quantitative analysis with total liver lipid extract. (E) Liver weight/bodyweight ratio, (F) serum lipid levels and (G) TNF-α levels (mean±SD, N ≥ 3, *P ˂ 0.05).
Figure 15.
Figure 15.
In vivo treatment of GW3965-modified material. (A) H&E staining and oil red O staining. Quantitative statistics of (B) lumen loss ratio and (C) lipid within the plaque (mean±SD, N ≥ 3, *P ˂ 0.05, ***P ˂ 0.001, ****P ˂ 0.0001).
Figure 16.
Figure 16.
Changes in signaling pathways of macrophages associated with atherosclerosis following treatment with LXR agonist-modified materials.
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