Surface Tensiometry of Apolipoprotein B Domains at Lipid Interfaces Suggests a New Model for the Initial Steps in Triglyceride-rich Lipoprotein Assembly

Apolipoprotein B (apoB) is the principal protein component of triacylglyceride (TAG)-rich lipoproteins, including chylomicrons and very low density lipoprotein, which is the precursor to LDL (the “bad cholesterol”). TAG-rich lipoprotein assembly is initiated by the N-terminal βα1 superdomain of apoB, which co-translationally binds and remodels the luminal leaflet of the rough endoplasmic reticulum. The βα1 superdomain contains four domains and is predicted to interact directly with lipids. Using drop tensiometry, we examined the interfacial properties of the α-helical and C-sheet domains and several subdomains to establish a detailed structure-function relationship at the lipid/water interface. The adsorption, stress response, exchangeability, and pressure (Π)-area relationship were studied at both triolein/water and triolein/1-palmitoyl, 2-oleoylphosphatidylcholine/water interfaces that mimic physiological environments. The α-helical domain spontaneously adsorbed to a triolein/water interface and formed a viscoelastic surface. It was anchored to the surface by helix 6, and the other helices were ejected and/or remodeled on the surface as a function of surface pressure. The C-sheet instead formed an elastic film on a triolein/water interface and was irreversibly anchored to the lipid surface, which is consistent with the behavior of amphipathic β-strands. When both domains were adsorbed together on the surface, the C-sheet shielded a portion of the α-helical domain from the surface, which retained its globular structure. Overall, the unique secondary and tertiary structures of the N-terminal domains of apoB support the intrinsic capability of co-translational lipid recruitment. The evidence presented here allows the construction of a detailed model of the initiation of TAG-rich lipoprotein assembly.     

脑梗死患者内脂素和基质金属蛋白酶-9 与颈动脉粥样硬化 斑块易损性的关系

目的：探讨血清内脂素（Visfatin）及基质金属蛋白酶-9（MMP-9）水平与脑梗死患者颈动脉粥样硬化斑块稳定性的关系和血 清visfatin 和MMP-9 的相关性。方法：选择脑梗死患者70 例,根据颈动脉粥样硬化斑块性质分为易损性斑块组(n=43)和非易损 性斑块组(n=27),选取健康体检者30 例作为对照组。测定血清Visfatin 和MMP-9 水平,并对二者间关系进行相关分析。结果：脑 梗死伴颈动脉硬化组血清Visfatin、MMP-9 水平高于正常对照组(P＜0.01);易损性斑块组血清Visfatin 和MMP-9 水平高于非易 损性斑块组,差异有统计学意义（P＜0.017）。外周血中的Visfatin水平与MMP-9 呈正相关关系（r=0.643,P=0.000）。结论：在脑梗 死患者中,血清Visfatin和MMP-9 参与了颈动脉粥样硬化的病理生理过程,Visfatin 和MMP-9升高可能与颈动脉粥样硬化斑块 不稳定性的形成相关,Visfatin 可通过调控MMP-9 的分泌和活性从而改变斑块的易损性。     

肿瘤坏死因子α刺激基因/诱导蛋白-6的抗炎作用研究进展

炎症损伤是众多临床疾病的病理学基础,常可引起严重并发症甚至导致死亡。然而传统临床治疗不仅方法有限,且效果不佳。近年研究报道,肿瘤坏死因子α刺激基因/诱导蛋白-6(tumor necrosis factor alpha stimulated gene/inducible protein 6, TSG-6)可通过与体内相应的配体结合参与炎症反应的多个过程,并发挥抗炎和促进细胞外基质重塑等重要作用。本文就TSG-6的生物学特性、作用机制及其在病理性瘢痕、神经炎症、动脉粥样硬化和关节炎等多种疾病中发挥的抗炎作用作一综述。     

Secretion of a new growth factor, smooth muscle cell derived growth factor, distinct from platelet derived growth factor by cultured rabbit aortic smooth muscle cells

In attempts to determine the mechanism of proliferation of arterial smooth muscle cells (SMC) in intimal atheromatous lesions, autocrine secretion of growth factors by SMC has recently received much attention. Here we report a new growth factor named smooth muscle cell derived growth factor (SDGF). Cultured rabbit medial SMC secreted SDGF for 1 week during their incubation in serum-free media only after at least 4 passages. SDGF differed from platelet derived growth factor (PDGF) physicochemically, immunologically, and biologically. The properties of SDGF also seemed different from those of other known growth factors that stimulate the proliferation of mesenchymal cells.     

Design,synthesis and pharmacology of aortic-selective acyl-CoA: Cholesterol O-acyltransferase (ACAT/SOAT) inhibitors

We describe our molecular design of aortic-selective acyl-coenzyme A:cholesterol O-acyltransferase (ACAT, also abbreviated as SOAT) inhibitors, their structure–activity relationships (SARs) and their pharmacokinetic (PK) and pharmacological profiles. The connection of two weak ligands—N-(2,6-diisopropylphenyl)acetamide (50% inhibitory concentration [IC₅₀]?=?8.6?μM) and 2-(methylthio)benzo[d]oxazole (IC₅₀?=?31?μM)—via a linker comprising a 6 methylene group chains yielded a highly potent molecule, 9-(benzo[d]oxazol-2-ylthio)-N-(2,6-diisopropylphenyl)nonanamide (3h) that exhibited high potency (IC₅₀?=?0.004?μM) toward aortic ACAT. This head-to-tail design made it possible to markedly enhance the activity to 2150- to 7750-fold and to discriminate the isoform-selectivity based on the double-induced fit mechanism. At doses of 1 and 3?mg/kg, 3h significantly decreased the lipid-accumulation areas in the aortic arch to 74 and 69%, respectively without reducing the plasma total cholesterol level in high fat- and cholesterol-fed F₁B hamsters. Here, we demonstrate the antiatherosclerotic effect of 3hin vivo via its direct action on aortic ACAT and its powerful modulator of cholesterol level. This molecule is a potential therapeutic agent for the treatment of diseases involving ACAT-1 overexpression.     

Measurement of coronary bifurcation angle with coronary CT angiography: A phantom study

PurposeAccurate determination of the bifurcation angle and correlation with plaque buildup may lead to the prediction of coronary artery disease (CAD). This work evaluates two techniques to measure bifurcation angles in 3D space using coronary computed tomography angiography (CCTA).Materials and MethodsNine phantoms were fabricated with different bifurcation angles ranging from 55.3° to 134.5°. General X-ray and CCTA were employed to acquire 2D and 3D images of the bifurcation phantoms, respectively. Multiplanar reformation (MPR) and volume rendering technique (VRT) were used to measure the bifurcation angle between the left anterior descending (LAD) and left circumflex arteries (LCx). The measured angles were compared with the true values to determine the accuracy of each measurement technique. Inter-observer variability was evaluated. The two techniques were further applied on 50 clinical CCTA cases to verify its clinical value.ResultsIn the phantom setting, the mean absolute differences calculated between the true and measured angles by MPR and VRT were 2.4° ± 2.2° and 3.8° ± 2.9°, respectively. Strong correlation was found between the true and measured bifurcation angles. Furthermore, no significant differences were found between the bifurcation angles measured using either technique. In clinical settings, large difference of 12.0° ± 10.6° was found between the two techniques.ConclusionIn the phantom setting, both techniques demonstrated a significant correlation to the true bifurcation angle. Despite the lack of agreement of the two techniques in the clinical context, our findings in phantoms suggest that MPR should be preferred to VRT for the measurement of coronary bifurcation angle by CCTA.     

INFLAM – INFLAMmation in Brain and Vessels with Iron Nanoparticles and Cell Trafficking: A Multiscale Approach of Tissue Microenvironment,Iron Nanostructure and Iron Biotransformation

Background

Inflammation is a share process in atherosclerosis and stroke and is thought to be a key player in the evolution of these diseases. Ten years ago, inflammation imaging with magnetic resonance imaging (MRI) was considered very promising for both pre-clinical and clinical studies of atherosclerosis and stroke.

Endothelial microparticles-mediated transfer of microRNA-19b promotes atherosclerosis via activating perivascular adipose tissue inflammation in apoE−/− mice

Microparticles(MPs) are the major carriers of circulating microRNAs. Our previous study has shown that microRNA (miR)-19b in endothelial cell-derived microparticles (EMPs) is significantly increased in patients with unstable angina. However, little is known about the relationship between miR-19b in EMPs and the progression of atherosclerosis. The aim of the present study was to define the role and potential mechanism of miR-19b incorporated in EMPs in the development of atherosclerosis.Western-diet-fed apoE^?/? mice were injected with phosphate buffered solution(PBS), EMP carrying microRNA control(EMP^control) or miR-19b mimic (EMP^miR19b) intravenously. Systemic treatment with EMP^miR19b significantly accelerated carotid artery atherosclerosis progression by increasing lipid, macrophages and smooth muscle cells and decreasing collagen content in atherosclerotic plaque. Fluorescence-labelled EMP^miR19b injection proved that miR-19b could be transported into perivascular adipose tissue(PVAT) by EMPs. EMP^miR19b treatment also promoted inflammatory cytokines secretion and macrophages infiltration in PVAT. In further experiment, apoE^?/? mice were divided into 3 groups: EMP^controlPVAT(+), EMP^miR19bPVAT(+) and EMP^miR19bPVAT(-), based on removing or keeping pericarotid adipose tissue and injected with EMP^control or EMP^miR19b. Loss of PVAT attenuated EMP^miR19b-mediated effects on increasing carotid atherosclerosis formation and inflammatory cytokines level in plaque. EMP^miR19b inhibited suppressor of cytokine signaling 3 (SOCS3) expression in PVAT. Our findings demonstrate that miR-19b in EMPs exaggerates atherosclerosis progression by augmenting PVAT-specific inflammation proceeded by downregulating SOCS3 expression.