Opportunities for an atherosclerosis vaccine: From mice to humans

Atherosclerosis, the major underlying cause of cardiovascular diseases (CVD), is the number one killer globally. The disease pathogenesis involves a complex interplay between metabolic and immune components. Although lipid-lowering drugs such as statins curb the risks associated with CVD, significant residual inflammatory risk remains. Substantial evidence from experimental models and clinical studies has established the role of inflammation and immune effector mechanisms in the pathogenesis of atherosclerosis. Several stages of the disease are affected by host-mediated antigen-specific adaptive immune responses that play either protective or proatherogenic roles. Therefore, strategies to boost an anti-atherogenic humoral and T regulatory cell response are emerging as preventative or therapeutic strategies to lowering inflammatory residual risks. Vaccination holds promise as an efficient, durable and relatively inexpensive approach to induce protective adaptive immunity in atherosclerotic patients. In this review, we discuss the status and opportunities for a human atherosclerosis vaccine. We describe (1) some of the immunomodulatory therapeutic interventions tested in atherosclerosis (2) the immune targets identified in pre-clinical and clinical investigations (3) immunization strategies evaluated in animal models (4) past and ongoing clinical trials to examine the safety and efficacy of human atherosclerosis vaccines and (5) strategies to improve and optimize vaccination in humans (antigen selection, formulation, dose and delivery).     

Apolipoprotein E e4 and its prevalence in early childhood death due to sudden infant death syndrome or to recognised causes

BACKGROUND:: Specific genetic polymorphisms have been shown to be more common in unexplained infant death. The APOE genotype exhibits opposite effects at the extremes of age with protective effects of e4 on perinatal mortality but detrimental effects as age progresses. OBJECTIVE:: To determine whether the APOE e4 allele is associated with early childhood (1 week-2 years) unexplained death ('sudden infant death syndrome', SIDS) or with recognised causes (non-SIDS) and to compare these cohorts with published perinatal and adult data. METHODS:: DNA was extracted from spleen tissue of children dying in South East Scotland between 1990 and 2002. APOE alleles (e2, e3, e4) were determined using PCR. Comparisons of allele frequencies between groups were made. RESULTS:: There were 167 SIDS cases and 117 non-SIDS cases. Allele distributions of SIDS cases were similar to healthy newborns. Allele distributions of non-SIDS cases were more similar to adults than to healthy newborns. The percentage of children with at least one e4 allele was significantly lower in non-SIDS compared to SIDS (p=0.016). Non-SIDS cases had a higher frequency of e3 compared to SIDS cases (p=0.01) and to healthy newborns (0.005). CONCLUSIONS:: Children dying from identified causes have different APOE allele distributions from SIDS cases, but are similar to adults. Children dying from SIDS have an allele distribution comparable to healthy newborns. The prevalence of e4 in SIDS is not of an order to contribute significantly to the age-related decline in e4.     

人血浆载脂蛋白AⅠ的纯化

 目的  初探大规模纯化人血浆载脂蛋白AⅠ(apolipoprotein AⅠ,ApoAⅠ）的低成本生产工艺。方法  以人血浆组分Ⅳ为原料,通过等电点沉淀、阴离子层析、低温乙醇沉淀和超滤等步骤纯化ApoAⅠ蛋白,并放大实验室纯化方法来纯化ApoAⅠ。结果  放大的纯化方法生产的ApoAⅠ的得率和纯度分别为59.0%和85.6%,经相关方法验证为人血浆ApoAⅠ。结论  实验室方法放大的纯化工艺可纯化ApoAⅠ。     

载脂蛋白A5基因的研究进展

血脂水平异常是冠心病、脑卒中等动脉粥样硬化性疾病的一个重要危险因素。血脂异常其实质是脂蛋白和载脂蛋白的异常。载脂蛋白A5基因自2001年被发现以来,证实其对调控三酰甘油水平有重要影响。现将载脂蛋白A5的结构功能、调控机制以及载脂蛋白A5基因单核苷酸多态性与血脂、冠心病的关系予以综述。     

Role of DNA damage in atherosclerosis--bystander or participant?

Atherosclerosis leading to cardiovascular disease is the leading cause of death among western populations. Atherosclerosis in characterised by the development of a fibrofatty lesion that consists of a diverse cell population, including inflammatory cells that create an intensely oxidising environment within the vessel. Coupled with normal replication, the local intracellular and extracellular environment causes damage to cellular DNA that is recognised and repaired by the DNA damage response (DDR) pathway. The role of DNA damage and the resulting deregulation of ‘normal’ cellular behaviour and subsequent loss of cell cycle control checkpoints have been widely studied in cancer. However, despite the extensive evidence for DNA damage in atherosclerosis, it is only over the past two decades that a causative link between DNA damage and atherosclerosis has been hypothesised. Whilst atherosclerosis is a feature of human disease characterised by defects in DNA damage, currently the role of DNA damage in the initiation and progression of atherosclerosis remains highly debated, as a ‘chicken and egg’ situation. This review will analyse the evidence for, the causes of, and consequences of DNA damage in atherosclerosis, detail the DNA damage response pathway that results in these consequences, and highlight therapeutic opportunities in this area. We also outline the evidence that DNA damage is a cause of both initiation and progression of atherosclerosis, and not just a consequence of disease.     

Pediatric fatty liver disease: Role of ethnicity and genetics

Non-alcoholic fatty liver disease (NAFLD) comprehends a wide range of conditions, encompassing from fatty liver or steatohepatitis with or without fibrosis, to cirrhosis and its complications. NAFLD has become the most common form of liver disease in childhood as its prevalence has more than doubled over the past 20 years, paralleling the increased prevalence of childhood obesity. It currently affects between 3% and 11% of the pediatric population reaching the rate of 46% among overweight and obese children and adolescents. The prevalence of hepatic steatosis varies among different ethnic groups. The ethnic group with the highest prevalence is the Hispanic one followed by the Caucasian and the African-American. This evidence suggests that there is a strong genetic background in the predisposition to fatty liver. In fact, since 2008 several common gene variants have been implicated in the pathogenesis of fatty liver disease. The most important is probably the patatin like phospholipase containing domain 3 gene (PNPLA3) discovered by the Hobbs’ group in 2008. This article reviews the current knowledge regarding the role of ethnicity and genetics in pathogenesis of pediatric fatty liver.     

Resolving the relationship between ApolipoproteinE and depression

Several studies have reported an association between the ApolipoproteinE-?4 (APOE4) allele and depression among elders. However others have failed to find an association. Since APOE4 is a well recognized risk factor for Alzheimer dementia, cognitive status may represent an important confounder between APOE4 and depression. In this investigation, we examined the relationship between the ApolipoproteinE-?4 allele and depression among elders accounting for cognitive status. Using a case-control design (n = 1052), we investigated the association between ApolipoproteinE-?4 and depression in Alzheimer disease patients (n = 528) and in cognitively intact controls (n = 524). We demonstrated an apparent association between the APOE4 allele and depression in the combined dataset (p = 0.001) when not controlling for cognitive status. However, once stratified by the presence of Alzheimer disease, there was no association in either the Alzheimer group (p = 0.290) or the cognitively intact controls (p = 0.494). In this dataset there is no association between the ApolipoproteinE-?4 allele and depression among those with Alzheimer disease or among cognitively intact elders. However there is a significant association between female gender and depression in the cognitively intact (p = 0.003) but not among those with Alzheimer disease. Additionally, individuals with Alzheimer disease and depression had a significantly younger age of onset for their Alzheimer disease than those without depression (p = 0.017).     

Impact of Serum Apolipoprotein A-IV as a Marker of Cardiovascular Disease in Maintenance Hemodialysis Patients

The aim of this study was to investigate the relationship between serum apolipoprotein (apo) A-IV levels and markers for atherosclerosis, including carotid intima-media thickness (CIMT) and the ankle–brachial index (ABI), in hemodialysis patients. We performed a cross-sectional study involving 116 maintenance hemodialysis patients (70 males; median age, 64 years), measuring CIMT, ABI, the usual laboratory examinations, and serum apo A-IV before the dialysis session. The apo A-IV concentration was measured by a noncompetitive ELISA. Serum apo A-IV concentrations were significantly lower in hemodialysis patients with cardiovascular disease and plaque in the carotid artery. The apo A-IV level was positively associated with urea nitrogen and creatinine, and negatively associated with age, interleukin-6, the neutrophil/lymphocyte ratio, and maximum CIMT. Moreover, serum apo A-IV concentrations were significantly lower in the low ABI group. On logistic analysis, patients with high apo A-IV levels had a lower odds ratio for atherosclerosis (maximum CIMT > 1.0) and cardiovascular disease compared to patients with low apo A-IV levels. On stepwise multivariate regression analysis, the serum apo A-IV level was independently associated with creatinine, the neutrophil/lymphocyte ratio, and the maximum CIMT. Serum apo A-IV is associated with atherosclerotic lesions in hemodialysis patients. Apo A-IV levels may be useful for estimating the risk of cardiovascular disease in dialysis patients.