Atherosclerosis Induced by a High-Cholesterol and High-Fat Diet in the Inbred Strain of the Wuzhishan Miniature Pig

Coronary artery disease has a significant genetic predisposition, which mainly results from atherosclerosis. Miniature pig is an excellent model to investigate atherosclerosis. This study investigated whether the occurrence and development of atherosclerosis in the Wuzhishan miniature pigs (WZSPs) that were closely bred 12 generations had better consistency. The WZSPs (n?=?9) were fed a high-cholesterol and high-fat diet (HCFD). After continuous feeding, 3 WZSPs each were sacrificed at 6, 8, and 12 months, respectively, and the general clinical manifestations and serological indexes were detected. The pathological changes of the major arteries and main organs were recorded. The results showed WZSPs were quite susceptible to the HCFD. At 6 months, plaque lesions appeared in the abdominal aorta and iliac artery, while at 8 months, they appeared in the coronary artery. At 12 months, atherosclerotic lesions could be found in all major arteries, while lipid core, cholesterol precipitation, and calcium deposition appeared in the most serious sites. The progression of arterial lesions and distribution of the lesions were highly consistent in the pigs. However, apparent variations in serum markers were observed. In conclusion, inbred WZSP is a good model to investigate atherosclerosis and has good predictability for the occurrence and development of the disease.     

The Yin and Yang of carbon nanomaterials in atherosclerosis

With unique characteristics such as high surface area, capacity of various functionalization, low weight, high conductivity, thermal and chemical stability, and free radical scavenging, carbon nanomaterials (CNMs) such as carbon nanotubes (CNTs), fullerene, graphene (oxide), carbon nanohorns (CNHs), and their derivatives have increasingly been utilized in nanomedicine and biomedicine. On the one hand, owing to ever-increasing applications of CNMs in technological and industrial fields as well as presence of combustion-derived CNMs in the ambient air, the skepticism has risen over the adverse effects of CNMs on human being. The influences of CNMs on cardiovascular system and cardiovascular diseases (CVDs) such as atherosclerosis, of which consequences are ischemic heart disease and ischemic stroke, as the main causes of death, is of paramount importance. In this regard, several studies have been devoted to specify the biomedical applications and cardiovascular toxicity of CNMs. Therefore, the aim of this review is to specify the roles and applications of various CNMs in atherosclerosis, and also identify the key role playing parameters in cardiovascular toxicity of CNMs so as to be a clue for prospective deployment of CNMs.     

Vascular smooth muscle cell proliferation as a therapeutic target. Part 2: Natural products inhibiting proliferation

Many natural products have been so far tested regarding their potency to inhibit vascular smooth muscle cell proliferation, a process involved in atherosclerosis, pulmonary hypertension and restenosis. Compounds studied in vitro and in vivo as VSMC proliferation inhibitors include, for example indirubin-3′-monoxime, resveratrol, hyperoside, plumericin, pelargonidin, zerumbone and apamin. Moreover, taxol and rapamycin, the most prominent compounds applied in drug-eluting stents to counteract restenosis, are natural products. Numerous studies show that natural products have proven to yield effective inhibitors of vascular smooth muscle cell proliferation and ongoing research effort might result in the discovery of further clinically relevant compounds.     

Electronegative LDL induces MMP-9 and TIMP-1 release in monocytes through CD14 activation: Inhibitory effect of glycosaminoglycan sulodexide

Objective

Electronegative LDL (LDL(?)) is involved in atherosclerosis through the activation of the TLR4/CD14 inflammatory pathway in monocytes. Matrix metalloproteinases (MMP) and their inhibitors (tissue inhibitors of metalloproteinase [TIMP]) are also crucially involved in atherosclerosis, but their modulation by LDL(?) has never been investigated. The aim of this study was to examine the ability of LDL(?) to release MMPs and TIMPs in human monocytes and to determine whether sulodexide (SDX), a glycosaminoglycan-based drug, was able to affect their secretion.

Endarterectomy patients with elevated levels of circulating IL-16 have fewer cardiovascular events during follow-up

Background and purposeIncreased interleukin 16 (IL-16) levels in carotid plaques have been associated with reduced incidence of cardiovascular (CV) events during follow-up in patients who underwent carotid endarterectomy (CEA). In the present study we aimed to determine whether high circulating levels of IL-16 also are associated with a decreased risk of CV events after CEA.MethodsPatients, who had their carotid plaques surgically removed (n = 473), were followed for a mean follow-up time of 3.1 years. Plasma levels of IL-16 the day before surgery were analyzed by proximity extension assay (PEA) and associated with the occurrence of CV events during follow-up (n = 98).ResultsHigh levels of circulating IL-16 were independently associated with a decreased risk of CV events when comparing the highest versus the lowest IL-16 tertile (hazard ratio [HR] 0.47; 95% CI 0.27–0.81; P = 0.007), as well as with CV deaths (HR 0.25; 95% CI 0.09–0.70; P = 0.008).ConclusionThese present findings indicate an association between IL-16 and less clinical complications of atherosclerosis in a population with known advanced carotid disease.     

Tolerization against atherosclerosis using heat shock protein 60

Atherosclerosis is a chronic inflammatory disease of the artery wall, and both innate and adaptive immunity play important roles in the pathogenesis of this disease. In several experimental and human experiments of early atherosclerotic lesions, it has been shown that the first pathogenic event in atherogenesis is intimal infiltration of T cells at predilection sites. These T cells react to heat shock protein 60 (HSP60), which is a ubiquitous self-antigen expressed on the surface of endothelial cells (ECs) together with adhesion molecules in response to classical risk factors for atherosclerosis. When HSP60 is expressed on the EC surface, it can act as a “danger-signal” for both cellular and humoral immune reactions. Acquired by infection or vaccination, beneficial protective immunity to microbial HSP60 and bona fide autoimmunity to biochemically altered autologous HSP60 is present in all humans. Thus, the development of atherosclerosis during aging is paid by the price for lifelong protective preexisting anti-HSP60 immunity by harmful (auto)immune cross-reactive attack on arterial ECs maltreated by atherosclerosis risk factors. This is supported by experiments, which shows that bacterial HSP60 immunization can lead and accelerate experimental atherosclerosis. This review article presents accumulating proof that supports the idea that tolerization with antigenic HSP60 protein or its peptides may arrest or even prevent atherosclerosis by increased production of regulatory T cells and/or anti-inflammatory cytokines. Recent data indicates that HSP60, or more likely some of its derivative peptides, has immunoregulatory functions. Therefore, these peptides may have important potential for being used as diagnostic agents or therapeutic targets.     

不同程度内质网应激对ApoE-/- 小鼠动脉粥样硬化斑块稳定性的影响

目的:采用Apo E-/-小鼠建立不稳定动脉粥样硬化斑块模型,给予不同剂量衣霉素,观察其对动脉粥样硬化斑块稳定性的影响。方法:取40只6-8周的Apo E-/-小鼠随机分为对照组和手术组。对照组小鼠给予正常饮食;手术组小鼠行右侧颈总动脉套管术(Perivascular carotid collar placement,PCCP),同时给予高脂喂养。9周末分别取对照组和手术组小鼠颈动脉,HE染色观察小鼠颈动脉斑块形成情况。成功造模后,将小鼠随机分为正常对照组、单纯PCCP组、小剂量衣霉素组和大剂量衣霉素组;正常对照组和单纯PCCP组给予生理盐水腹腔注射,小剂量衣霉素组和大剂量衣霉素组分别给予小剂量衣霉素、大剂量衣霉素腹腔注射。2周后,处死小鼠,通过HE染色观察颈动脉斑块形态,油红O染色观察斑块内脂质聚集,抗巨噬细胞免疫组化染色观察斑块内巨噬细胞聚集,Western-blot检内质网应激标志蛋白GRP78和自噬标志蛋白Atg7、P62的表达水平。结果:HE染色结果显示:与单纯PCCP组和大剂量衣霉素组相比,小剂量衣霉素组颈动脉腔内的斑块脂质池减少,斑块结构较为完整且相对稳定;油红O染色结果显示:小剂量衣霉素组斑块内脂质含量显著降低(P0.05 vs单纯PCCP组和大剂量衣霉素组);巨噬细胞免疫组化染色显示:与单纯PCCP组和大剂量衣霉素组相比,小剂量衣霉素组斑块内巨噬细胞的含量显著降低(P0.05);Western-blot结果显示:小剂量衣霉素干预诱导的一定程度的内质网应激可以适度上调自噬(P0.05 vs单纯PCCP组和大剂量衣霉素组)。结论:PCCP手术加高脂饮食可以短期成功建立小鼠不稳定动脉粥样硬化斑块模型,其动脉粥样硬化斑块不稳定性较高,而小剂量衣霉素干预可以使得颈动脉管腔内斑块相对较小,内部脂质池明显较小,纤维帽变厚且结构更完整,斑块结构较稳定;斑块内脂质含量降低;巨噬细胞含量明显降低,且小剂量衣霉素组自噬水平适度上调。因此,小剂量衣霉素干预引起的适度的内质网应激一定程度对动脉粥样硬化斑块起到保护作用。     

Hcy, hs-CRP与急性脑梗死患者颈动脉粥样硬化关系的研究

目的:探讨急性脑梗死患者血清同型半胱氨酸(Hcy)、超敏C反应蛋白(hs-CRP)与颈动脉粥样硬化的相关性及临床意义。方法:收集确诊为急性脑梗死患者90例,对患者进行颈动脉超声检查,根据颈动脉狭窄程度将患者分成颈动脉内膜正常组、轻度狭窄组、中-重度狭窄组。比较三组患者斑块检出率、Hcy、hs-CRP水平和IMT厚度,同时对Hcy、hs-CRP与IMT进行相关性分析。结果:中-重度狭窄组斑块检出率为86.4%,显著高于轻度狭窄组和颈动脉内膜正常组(P0.05);颈动脉内膜正常组Hcy、hs-CRP水平以及IMT厚度均显著低于颈动脉轻度狭窄组、中-重度狭窄组(P0.05);hs-CRP与IMT呈正相关(r=0.71,P0.05);Hcy与IMT呈正相关(r=0.79,P0.05)。结论:血清Hcy和hs-CRP水平与颈动脉粥样硬化程度密切相关,Hcy、hs-CRP联合检测对急性脑梗死的早期诊断和预后有着重要临床意义。     

动脉粥样硬化大鼠心肌梗死时钙敏感受体表达的变化及其作用机制

目的:探讨动脉粥样硬化大鼠心肌梗死时钙敏感受体表达的变化及其作用机制。方法:Wistar大鼠随机分为4组:正常对照组(Control);异丙肾上腺组(ISO);动脉硬化组(AS);动脉硬化+异丙肾上腺素组(AS/ISO)。采用腹腔注射VD3和高脂饮食及大剂量异丙肾上腺素(ISO 200 mg/kg)皮下注射复制大鼠在体动脉粥样硬化心肌梗死模型,应用RT-PCR测定心肌组织中Ca SR、Bax、Bcl-2和caspase-3 m RNA的表达变化;TUNEL染色观察心肌细胞凋亡情况;光镜观察心肌形态学变化;紫外分光法检测血清肌酸激酶(CK)、电化学免疫发光法检测肌钙蛋白T(c Tn T)水平。结果:与正常组比较,ISO组CK活性、c Tn T水平以及Ca SR、Bax和caspase-3的表达均增加,同时Bcl-2表达减少,心肌细胞损伤严重,AS/ISO的心肌损伤进一步加重。结论:Ca SR的表达增多参与了动脉硬化大鼠心肌梗死的发生,其机制可能与促进心肌细胞凋亡有关。     

Mulberry leaf powder prevents atherosclerosis in apolipoprotein E-deficient mice

Mulberry is commonly used to feed silkworms. Here we examined whether a dietary intake of mulberry leaf (ML) could affect atherogenesis in vivo and in vitro. Apolipoprotein E-deficient mice were fed either normal chow (control group) or a diet containing 1% ML powder (ML group) from 6 weeks of age. The mice were sacrificed after 12 weeks. The susceptibility of plasma lipoprotein to oxidation was assessed using diene formation. A significant increase in the lag time of lipoprotein oxidation was detected in the ML group compared with the control group. Furthermore, the ML group showed a 40% reduction in atherosclerotic lesion size in the aortae compared with the control. We also examined the direct anti-oxidative activity of ML in vitro. Aqueous extract of ML had a strong scavenging effect on 1,1-diphenyl-2-picrylhydrazyl and inhibited lipoprotein oxidation. These results confirm that ML contains anti-oxidative substances that might help prevent atherosclerosis.