Oxidized low-density lipoprotein-induced foam cell formation is mediated by formyl peptide receptor 2

The increased level of LDL and its modification into oxLDL has been regarded as an important risk factor for the development of cardiovascular diseases such as atherosclerosis. Although some scavenger receptors including CD36 and RAGE have been considered as target receptors for oxLDL, involvement of other receptors should be investigated for oxLDL-induced pathological responses. In this study, we found that oxLDL-induced foam cell formation was inhibited by formyl peptide receptor 2 (FPR2) antagonist WRW⁴. oxLDL also stimulated calcium signaling and chemotactic migration in FPR2-expressing RBL-2H3 cells but not in vector-expressing RBL-2H3 cells. Moreover, oxLDL stimulated TNF-α production, which was also almost completely inhibited by FPR2 antagonist. Our findings therefore suggest that oxLDL stimulates macrophages, resulting in chemotactic migration, TNF-α production, and foam cell formation via FPR2 signaling, and thus likely contributes to atherogenesis.     

A multiscale study on the structural and mechanical properties of the luffa sponge from Luffa cylindrica plant

Cellular materials that are often observed in biological systems exhibit excellent mechanical properties at remarkably low densities. Luffa sponge is one of such materials with a complex interconnecting porous structure. In this paper, we studied the relationship between its structural and mechanical properties at different levels of its hierarchical organization from a single fiber to a segment of whole sponge. The tensile mechanical behaviors of three single fibers were examined by an Instron testing machine and the ultrastructure of a fractured single fiber was observed in a scanning electronic microscope. Moreover, the compressive mechanical behaviors of the foam-like blocks from different locations of the sponge were examined. The difference of the compressive stress–strain responses of four sets of segmental samples were also compared. The result shows that the single fiber is a porous composite material mainly consisting of cellulose fibrils and lignin/hemicellulose matrix, and its Young?s modulus and strength are comparable to wood. The mechanical behavior of the block samples from the hoop wall is superior to that from the core part. Furthermore, it shows that the influence of the inner surface on the mechanical property of the segmental sample is stronger than that of the core part; in particular, the former?s Young?s modulus, strength and strain energy absorbed are about 1.6 times higher. The present work can improve our understanding of the structure–function relationship of the natural material, which may inspire fabrication of new biomimetic foams with desirable mechanical efficiency for further applications in anti-crushing devices and super-light sandwich panels.     

Angptl 4 deficiency improves lipid metabolism, suppresses foam cell formation and protects against atherosclerosis

Angiopoietin-like protein family 4 (Angptl 4) has been shown to regulate lipoprotein metabolism through the inhibition of lipoprotein lipase (LPL). We generated ApoE^−/−Angptl 4^−/− mice to study the effect of Angptl 4 deficiency on lipid metabolism and atherosclerosis. Fasting and postolive oil-loaded triglyceride (TG) levels were largely decreased in ApoE^−/−Angptl 4^−/− mice compared with and ApoE^−/−Angptl 4^+/+ mice. There was a significant (75 ± 12%) reduction in atherosclerotic lesion size in ApoE^−/−Angptl 4^−/− mice compared with ApoE^−/− Angptl 4^+/+ mice. Peritoneal macrophages, isolated from Angptl 4^−/− mice to investigate the foam cell formation, showed a significant decrease in newly synthesized cholesteryl ester (CE) accumulation induced by acetyl low-density lipoprotein (acLDL) compared with those from Angptl 4^+/+ mice. Thus, genetic knockout of Angptl 4 protects ApoE^−/− mice against development and progression of atherosclerosis and strongly suppresses the ability of the macrophages to become foam cells in vitro.     

Rimonabant is a dual inhibitor of acyl CoA:cholesterol acyltransferases 1 and 2

Acyl coenzyme A:cholesterol acyltransferase (ACAT) catalyzes the intracellular synthesis of cholesteryl esters (CE). Both ACAT isoforms, ACAT1 and ACAT2, play key roles in the pathophysiology of atherosclerosis and ACAT inhibition retards atherosclerosis in animal models. Rimonabant, a type 1 cannabinoid receptor (CB1) antagonist, produces anti-atherosclerotic effects in humans and animals by mechanisms which are not completely understood. Rimonabant is structurally similar to two other cannabinoid receptor antagonists, AM251 and SR144528, recently identified as potent inhibitors of ACAT. Therefore, we examined the effects of Rimonabant on ACAT using both in vivo cell-based assays and in vitro cell-free assays. Rimonabant dose-dependently reduced ACAT activity in Raw 264.7 macrophages (IC₅₀ = 2.9 ± 0.38 μM) and isolated peritoneal macrophages. Rimonabant inhibited ACAT activity in intact CHO-ACAT1 and CHO-ACAT2 cells and in cell-free assays with approximately equal efficiency (IC₅₀ = 1.5 ± 1.2 μM and 2.2 ± 1.1 μM for CHO-ACAT1 and CHO-ACAT2, respectively). Consistent with ACAT inhibition, Rimonabant treatment blocked ACAT-dependent processes in macrophages, oxysterol-induced apoptosis and acetylated-LDL induced foam cell formation. From these results we conclude that Rimonabant is an ACAT1/2 dual inhibitor and suggest that some of the atherosclerotic beneficial effects of Rimonabant are, at least partly, due to inhibition of ACAT.     

Oxidative modification of low-density lipoprotein and immune regulation of atherosclerosis

Oxidized low-density lipoprotein (oxLDL) is thought to promote atherosclerosis through complex inflammatory and immunologic mechanisms that lead to lipid dysregulation and foam cell formation. Recent findings suggested that oxLDL forms complexes with β₂-glycoprotein I (β₂GPI) and/or C-reactive protein (CRP) in the intima of atherosclerotic lesions. Autoantibodies against oxLDL/β₂GPI complexes occur in patients with systemic lupus erythematosus (SLE) and/or antiphospholipid syndrome (APS) and significantly correlate with arterial thrombosis. IgG autoantibodies having similar specificity emerged spontaneously in non-immunized NZW × BXSB F1 mice, an animal model of APS, and a monoclonal autoantibody (WB-CAL-1; IgG2a) against complexed β₂GPI (oxLDL/β₂GPI complexes) was derived from the same mice. WB-CAL-1 significantly increased the in vitro uptake of oxLDL/β₂GPI complexes by macrophages. This observation strongly suggests that such IgG autoantibodies are pro-atherogenic. In contrast, IgM anti-oxLDL natural antibodies found in the atherosclerosis-prone mice (ApoE^-/- and LDL-R^-/- mice) have been proposed to be anti-atherogenic (protective). The presence of IgG anti-oxLDL antibodies in humans has been documented in many publications but their exact clinical significance remains unclear. In this article, we review recent progress in our understanding of the mechanisms involved in oxidation of LDL, formation of oxLDL complexes, and antibody mediated-immune regulation of atherogenesis.     

Differential regulation of the STARD1 subfamily of START lipid trafficking proteins in human macrophages

The STARD1 subfamily of ‘START’ lipid trafficking proteins can reduce macrophage lipid content and inflammatory status (STARD1; StAR), and traffic cholesterol from endosomes (STARD3/MLN64). During macrophage differentiation, STARD1 mRNA and protein increase with sterol content, while the reverse is true for STARD3. Sterol depletion (methyl beta-cyclodextrin) enhances STARD3, and represses STARD1 expression. Agonists of Liver X receptors, peroxisome proliferator activated receptor-gamma and retinoic acid X receptors increase STARD1 expression, while hypocholesterolaemic agent, LY295427, reveals both STARD1 and STARD3 as putative SREBP-target genes. Pathophysiological ‘foam cell’ formation, induced by acetylated or oxidized LDL, significantly reduced both STARD1 and STARD3 gene expression. Differential regulation of STARD1 and D3 reflects their distinct roles in macrophage cholesterol metabolism, and may inform anti-atherogenic strategies.     

Influence of foam thickness on the control of EMG activity during a step-down task in females

Compliant foams can be used to mitigate ground reaction forces. However, it is unknown how foam surfaces influence the modulation of leg muscle activity. Thus, the current study aimed to investigate how the neuromuscular system managed changes in expected loading due to various thickness of foam placed on the landing surface during a step down task. The surface electromyographic signal (sEMG) pre-activation duration and the root mean square (RMS) amplitude of tibialis anterior (TA), lateral gastrocnemius (LG), and vastus medialis (VM) of 10 active females were measured as they stepped-down with a single leg onto polyurethane foam slabs of varying thickness (0–50 mm). Pre-activation duration was not affected by the thickness of the foam padding. LG RMS amplitude was less in the foam conditions than the control (no– foam) condition, with the greatest reduction observed for the 50 mm foam condition. In some trials, the muscles remained active throughout the step-down task. In such instances, a sEMG onset time and thus a pre-activation duration could not be determined. All foam conditions significantly increased the odds of continuous muscle activity above that of the no-foam condition. The results indicate that foam surfaces may alter the modulation of muscle activity during step-down tasks.     

Fabrication and characterisation of α-chitin nanofibers and highly transparent chitin films by pulsed ultrasonication

α-Chitin nanofibers were fabricated with dried shrimp shells via a simple high-intensity ultrasonic treatment under neutral conditions (60 KHz, 300 W, pH = 7). The diameter of the obtained chitin nanofibers could be controlled within 20–200 nm by simply adjusting the ultrasonication time. The pulsed ultrasound disassembled natural chitin into high-aspect-ratio nanofibers with a uniform width (19.4 nm after 30 min sonication). The EDS, FTIR, and XRD characterisation results verified that α-chitin crystalline structure and molecular structure were maintained after the chemical purification and ultrasonic treatments. Interestingly, ultrasonication can slightly increase the degree of crystallinity of chitin (from 60.1 to 65.8). Furthermore, highly transparent chitin films (the transmittance was 90.2% at a 600 nm) and flexible ultralight chitin foams were prepared from chitin nanofiber hydrogels.     

Oxidized LDL-induced endolysosomal phospholipidosis and enzymatically modified LDL-induced foam cell formation determine specific lipid species modulation in human macrophages

Recruitment of circulating monocytes and formation of macrophage foam cells in the arterial intima are characteristic features of atherogenesis. Foam cells are formed by cellular uptake and storage of atherogenic lipoproteins, including oxidized LDL (oxLDL) and enzymatically modified LDL (eLDL). Dissection of oxLDL- and eLDL-induced cellular phenotypes indicates that these two LDL-modifications are coupled with two fundamentally different cellular responses in macrophages. Oxidized LDL preferentially up-regulates scavenger receptors required for its internalization, induces preferential lipid storage in the acidic compartment resembling drug-induced endolysosomal phospholipidosis, parallel with increased cellular content of the endolysosomal signature lipid bis(monoacylglycero)phosphate, pro-apoptotic signalling and appearance of ceramide-enriched surface membrane microdomains. By contrast, challenge of macrophages by eLDL leads to expanded cholesterol- and sphingomyelin-enriched surface membrane microdomains, up-regulation of diverse pattern recognition receptors required for phagocytosis of eLDL, parallel with extensive lipid droplet formation, increased endoplasmic reticulum (ER)-stress and membrane contact site formation for interorganelle trafficking and signalling, and enhanced cellular content of the mitochondrial lipid cardiolipin.This review focuses on biological activities of oxLDL and eLDL in human macrophages, and discusses some lipidomic considerations related to foam cell formation and phospholipidosis.