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Cardiovascular disease, which is often driven by hypercholesterolemia and subsequent coronary atherosclerosis, is the number-one cause of morbidity and mortality in the United States. Based on long-term epidemiological studies, high-density lipoprotein cholesterol (HDL-C) levels are inversely correlated with risk for coronary artery disease (CAD). HDL-mediated reverse cholesterol transport (RCT) is responsible for cholesterol removal from the peripheral tissues and return to the liver for final elimination.1 In atherosclerosis, intraplaque angiogenesis promotes plaque growth and increases plaque vulnerability. Conceivably, the acceleration of RCT and disruption of intraplaque angiogenesis would inhibit atherosclerosis and reduce CAD. We have identified a protein called apoA-I binding protein (AIBP) that augments HDL functionality by accelerating cholesterol efflux. Furthermore, AIBP inhibits vascular endothelial growth factor receptor 2 activation in endothelial cells and limits angiogenesis.2 The following discusses the prospect of using AIBP as a novel therapeutic approach for the treatment of CAD. 相似文献
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LDL (Low Density Lipoprotein) is considered the major atherogenic lipoprotein whereas HDL (High Density Lipoprotein) is anti-atherogenic. In recent years also non-HDL cholesterol as well as TG (triglycerides) are included in guidelines defining cardiovascular (CV) risk and target values during lipid lowering treatment. In recent years apolipoproteins (apo) B, reflecting atherogenic, and apoA-I reflecting anti-atherogenic lipoproteins, have been shown to be superior to conventional lipids in predicting risk and reduction of events in lipid lowering trials using statins. These new data are reviewed. The apoB/apoA-I ratio, which reflects the cholesterol balance of the “bad” and “good” lipids, is a simple and accurate summary index of CV risk and it is better than the conventional LDL and other lipids as a risk marker and taget for therapy. 相似文献
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During the last several years interest has focused on the importance of the lipid-transporting apolipoproteins--apoB transports all potentially atherogenic very low-density lipoprotein (VLDL), intermediate-density lipoprotein (IDL) and LDL particles, and apoA-I transports and acts as the major antiatherogenic protein in the HDL particles. The evidence for the apoB/apoA-I ratio being a strong, new risk factor for cardiovascular (CV) disease and a target for lipid-lowering therapy is reviewed. Results from clinical prospective studies and lipid-lowering trials in healthy subjects and in patients with different clinical manifestations of atherosclerosis are reported. Risk of nonfatal and fatal myocardial infarction and stroke, and manifestations of atherosclerosis documented by angiographic, ultrasound and other techniques has been related to conventional lipids and apolipoproteins (apo). The cholesterol balance determined as the apoB/apoA-I ratio has repeatedly been shown to be a better marker than lipids, lipoproteins and lipid ratios. The results indicate that the apoB/apoA-I ratio is a simple, accurate and new risk factor for CV disease--the lower the apoB/apoA-I ratio, the lower is the risk. Guidelines should be developed in order to recognize the important clinical risk information embedded in the apoB/apoA-I ratio. 相似文献
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Tiziana Bacchetti Simona Masciangelo Tatiana Armeni Virginia Bicchiega Gianna Ferretti 《Metabolism: clinical and experimental》2014
Objective
Methylglyoxal (MG), a reactive carbonyl compound formed primarily from triose phosphates, appears to be involved in the molecular mechanisms of diabetes, end-stage renal disease and neurodegenerative diseases. Methylglyoxal exerts several biological activities. Among these it promotes advanced glycation end products (AGEs), which are crucial in pathogenesis of human disease. Previous studies have demonstrated that MG reacts with proteins and compositional modifications reflect loss of biological activity. The aim of the study was to investigate the effect of in vitro MG-induced glycation on human high density lipoprotein (HDL) and on the activity of the enzyme paraoxonase-1 (PON1).Methods
HDL was incubated in the absence or in the presence of MG (0.2 mmol/L and 1.0 mmol/L) (MG-HDL) for different times (3, 6, 24 h) at 37 ° C. We evaluated apoprotein compositional changes, in both control and MG treated HDL, using intrinsic fluorescence of tryptophan and monitoring the decrease of free amino groups. Furthermore we evaluated fluorescent advanced glycation end products (Ex = 370 nm, Em = 440 nm) and the activity of HDL-paraoxonase.Results
We demonstrated that human HDL is susceptible to glycation by MG (0.2 mmol/L and 1 mmol/L). The decrease of free amino groups and of intrinsic fluorescence of tryptophan demonstrates HDL apoprotein modifications in HDL incubated with MG. The compositional changes are associated with a significant increase in fluorescent advanced glycation end products and with a significant decrease of paraoxonase-1 enzyme activity associated with the HDL surface.Conclusions
HDL-associated paraoxonase is responsible for the anti-inflammatory and anti-oxidative properties of HDL and detoxification against homocysteine-thiolactone. Therefore, modifications of apoprotein composition and the decrease of paraoxonase-1 activity in MG-treated HDL could affect the protective effect exerted by HDL against oxidative damage and could contribute to complications in patients affected by diseases associated with aging and oxidative stress. 相似文献6.
BACKGROUND: Viruses, among them parvovirus B19 and other small, nonenveloped viruses, may be present in human blood and may contaminate plasma-derived therapeutics. Efficient inactivation or removal of such viruses, especially parvoviruses, represents a current problem and corresponding technologies are under investigation. In this report, such a technology is described. STUDY DESIGN AND METHODS: A recently developed pasteurization of human apolipoprotein A-I (apoA-I), which is performed at 60 degrees C for 10 hours in the presence of guanidine hydrochloride (GdnHCl), was validated by using a series of model viruses, including members of the families parvoviridae and picornaviridae. The model viruses were spiked into the apoA-I- and GdnHCl-containing solutions, and virus inactivation was evaluated by infectivity assays in cell cultures. The mechanism of virus inactivation was studied by virus sedimentation analysis using the picornavirus model. RESULTS: All viruses tested were inactivated to levels below the limit of detection, although different inactivation kinetics were obtained for the different viruses. The mechanism of virus inactivation by this pasteurization was disassembly of the virus particles into single proteins or small noninfectious viral subunits. CONCLUSION: The pasteurization validated in this report has the potential to inactivate a wide range of transfusion-relevant viruses including parvoviruses and picornaviruses. 相似文献
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目的 探究护心通络方通过调控胆固醇脂转运蛋白(CETP)抗兔动脉粥样硬化(AS)的效果及作用机制。方法 将40只雄性新西兰兔按照随机数字表法分为空白对照组、AS模型组、辛伐他汀组[0.33 mg/(kg·d)]、护心通络方组[0.34 g/(kg·d)],每组10只。空白对照组予普通饲料喂养22周,其他3组予高脂饲料喂... 相似文献
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Lorenzi I von Eckardstein A Cavelier C Radosavljevic S Rohrer L 《Journal of molecular medicine (Berlin, Germany)》2008,86(2):171-183
Accumulation of lipid-loaded macrophages (foam cells) within the vessel wall is an early hallmark of atherosclerosis. High-density lipoproteins (HDL) and apolipoprotein A-I (apoA-I) can efficiently promote cholesterol efflux from macrophages. Therefore, the interaction of HDL and apoA-I with macrophages appears to be important in the initial steps of reverse cholesterol transport, i.e. the transport of excess cholesterol from foam cells to the liver. However, although several cellular apoA-I and HDL receptors and transporters have been identified, it is as yet controversial how these interactions lead to cholesterol efflux from foam cells. In this study, we show that RAW264.7 macrophages bind HDL and apoA-I in a compatible manner. Furthermore, cell surface biotinylation experiments revealed that apoA-I but not HDL is specifically internalised. Binding of HDL to macrophages is decreased by reducing the expression of scavenger receptor BI (SR-BI) with cyclic adenosine monophosphate (cAMP), acetylated low-density lipoprotein (acLDL) or RNA interference. In contrast, apoA-I cell association and internalisation is modulated in parallel with ATP-binding cassette transporter A1 (ABCA1) expression which is altered by stimulating cells with cAMP and acLDL or expressing short hairpin RNA (shRNA) against ABCA1. Consistent with this, cell surface trapping of ABCA1 with cyclosporin A (CsA) results in increased apoA-I binding but reduced internalisation. Furthermore, blocking apoA-I uptake inhibits cholesterol efflux to apoA-I but not to HDL. Taken together, these data suggest that apoA-I- but not HDL-mediated cholesterol efflux may involve retroendocytosis. 相似文献
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