Expression of heat shock protein–70 by dendritic cells in the arterial intima and its potential significance in atherogenesis

AbstractObjective: Overexpression of heat shock proteins (HSPs) is an important means of cell protection during physiologic stress such as occurs during atherogenesis. Immune responses are early events in atherosclerosis, with recent studies indicating that both humoral and cellular autoimmune processes in atherogenesis are directed toward HSPs. Dendritic cells are the key cells in the initiation and regulation of immune responses. This study examined whether HSP70 is overexpressed by dendritic cells in atherosclerotic lesions. Methods: Twenty-six carotid artery and 16 aortic specimens obtained at endarterectomy and aortic reconstruction were examined with immunohistochemical techniques. The nature of cells that overexpressed HSP70 was studied in consecutive sections that were double stained with antibodies to HSP70 and cell type–specific markers, including CD1a and fascin (to identify dendritic cells), CD14 (monocytes), CD68 (macrophages), CD3 (T cells), CD15 (mast cells), von Willibrand factor (endothelial cells), and α–smooth muscle actin (smooth muscle cells). Staining with HLA-DR and CD1d was used to identify cells involved in antigen presentation. Results: In advanced atherosclerotic lesions, several cell types, including monocytes, macrophages, dendritic cells, and smooth muscle cells, overexpressed HSP70. In contrast, in early atherosclerotic lesions, only dendritic cells overexpressed HSP70. Dendritic cells that overexpressed HSP70 frequently contacted T cells and also expressed HLA-DR. Furthermore, dendritic cells that clustered with T cells expressed CD1d, a unique molecule responsible for presenting lipid antigens. Conclusion: The results suggest that direct contacts between activated dendritic cells that overexpress HSP70 and T cells might be responsible for T cell activation and might facilitate the presentation of lipid antigens to T cells directly within the arterial wall. In early intimal lesions, HSP70 is overexpressed exclusively by dendritic cells, which suggests that dendritic cells might be involved in the early phases of atherogenesis. (J Vasc Surg 2002;35:368-75.

Cell Composition of the Subendothelial Aortic Intima and the Role of Alpha-Smooth Muscle Actin Expressing Pericyte-Like Cells and Smooth Muscle Cells in the Development of Atherosclerosis

The cell composition of the human arterial intima has been intensely studied but is still not well understood. The majority of cell population in normal and atherosclerotic intima is represented by cells expressing smooth muscle α-actin, which are thought to be smooth muscle cells. Some antigens, which are absent in medial smooth muscle cells, were detected in intimal smooth muscle cells. In particular, using 3G5 antipericyte antibody, presence of stellate-shaped pericyte-like resident cells in normal and atherosclerotic human aortic intima has been found. In all analyzed aortic tissue specimens, 3G5+ cells were found to account for more than 30% of the total intimal cell population of undiseased intima. In the atherosclerotic lesions, the number of 3G5+ cells becomes notably lower than that in undiseased intima. The use of 2A7 antibody that identifies activated pericytes revealed the presence of 2A7+ cells in atherosclerotic plaques, while no 2A7+ cells were detected in normal intima. The strongest correlation was established between the number of pericyte-like cells and the content of intimal lipids. The correlation coefficients between the number of pericyte-like cells and collagen content and intimal thickness were greater than the correlation coefficients for smooth muscle cells. On the basis of these findings, pericyte-like cells but not smooth muscle cells or other cell types have been declared to be the key cellular element driving the formation of atherosclerotic lesions. The present chapter aims to detail the abovementioned issues. The present chapter also aims to promote a view that α-smooth muscle actin+ pericyte-like cells represent the key players in the development of atherosclerotic lesions

Use of Natural Products for Direct Anti-Atherosclerotic Therapy

Atherosclerosis and vascular disorders, which result from atherosclerosis, represent one of the major problems in the modern medicine and public health. Atherosclerosis is characterized by structural and functional changes of large arteries. The approaches for the treatment of atherosclerosis require at least the prevention of growth of atherosclerotic lesions and reduction in the lipid core mass, which would followed by plaque stabilization. Taken together, these approaches could theoretically result in the regression of arterial lesions. Atherosclerosis develops in the arterial wall and remains asymptomatic until ischemia of distal organs is evident. Therapy of clinical manifestations of atherosclerosis is largely aimed at reducing symptoms or affecting hemodynamic response and often does not affect the cause or course of disease, namely the atherosclerotic lesion itself. Of course, anti-atherosclerotic effects of statins revealed in many prospective clinical trials may be considered; however, statins have never been recognized as the drugs indicated just for direct treatment or prevention of atherosclerosis. They are used predominately in the course of hypolipidemic therapy, and the effects of treatment are estimated by success in reaching the target level of low density lipoprotein (LDL) cholesterol, but not the regression of atherosclerotic lesion or intimamedia thickness. The last should be considered as beneficial effect, which is mainly due to pleiotropic mechanisms of action. Atherosclerosis develops over many years, so anti-atherosclerotic therapy should be a long-term or even lifelong therapy. Tachyphylaxis, long-term toxicity and cost amongst other issues may present problems for the use of conventional medications in a long-term. Drugs based on natural products can be a good alternative

The effect of maximal vs submaximal exertion on postprandial lipid levels in individuals with and without coronary heart disease

Background: Decisions about fat consumption and levels of physical activity are among the everyday choices we make in life and risk of coronary heart disease (CHD) can be affected by those choices. Objective: The purpose of this study was to investigate the influence of a standard fat load combined with physical exertion of different intensities on the plasma lipid profile of CHD patients and CHD-free individuals. Methods: This study looked at the influence of different intensities of physical exercise on postprandial lipid metabolism in 20 healthy men and 36 men with diagnosis of CHD. Venous blood samples were obtained after overnight fasting, 3 hours after standard fat load (before the physical load), and immediately after maximal or submaximal physical exercise on bicycle ergometer. Results: After fat load total cholesterol (TC) concentration did not change in either group. However, after the addition of maximal exercise, TC, triglycerides (TG), low-density lipoprotein cholesterol (LDL-C), and apolipoprotein (Apo) B increased significantly (P < .01) in both groups. After fat load and maximal exercise, there was no change in high-density lipoprotein cholesterol (HDL-C) in healthy men, but in men with CHD, HDL-C fell significantly (P < .01); and Apo AI rose in healthy men (P < .01) but dropped significantly (P < .01) in men with CHD. Submaximal physical exercise (60% of max VO2 load for 40 minutes) after fat load decreased TG level in CHD patients (P < .01) and improved other lipid parameters in both groups significantly (↓LDL-C, ↑HDL-C, ↑Apo AI, ↓Apo B, P < .01). We observed a worsening of physical work capacity in men with CHD (significant reduction of duration and total amount of work performed, maximal VO2, oxygen pulse), during maximal stress test performed 3 hours after fat load. There was a doubling of the number of abnormal stress test results (P < .01). Healthy persons showed an increase in respiratory parameters (ventilation, CO2 production, maximal VO2, and oxygen pulse), but no significant change was found in work capacity. Thus, maximal physical exercise produced atherogenic blood lipid changes (increased TC, increased LDL-C, increased TG, increased Apo B, P < .01) in men with CHD and in healthy men; however, individuals with CHD also demonstrated a significant decrease in HDL-C and Apo AI (P < .01). In contrast, the submaximal physical load improved postprandial lipid changes in both healthy men and men with CHD. Conclusions: This study demonstrates that moderate exercise is beneficial in improving postprandial lipid abnormalities in both CHD and CHD-free subjects after fatty meal preload. In addition, maximal exercise demonstrated evidence of increase of lipid abnormalities in both CHD and CHD-free individuals under similar conditions of fatty meal preload

Knowledge of Malaysian university students towards swine-origin influenza A (H1N1) virus: A qualitative study

Introduction: The study was aimed to explore the knowledge towards swine flu among university students.Methods: An in-depth interview was conducted among 40 Students chosen randomly and asked to participate. The interviewers followed a standardized protocol to ensure that all the participants’ interviews were conducted in a similar manner and that an identical set of questions were discussed.  Due to the small sample size, the data was analyzed manually.Results: The majority of the participants were aware that H1N1 is a disease caused by Influenza A virus subtype H1N1. In terms of transmission, the majority of participants believed that the H1N1 might be transmitted from an infected person to a susceptible person; 12 out of 40 students thought that people might be infected by eating pork meat. Few students reported that the pig farmers and those in close contact with pigs were at high risk of the infection. Regarding preventions, half of the participants reported that H1N1 infection might be prevented by wearing face-masks, washing hands and avoiding close contact with infected patients.Conclusion: Despite majority of the participants had the basic knowledge regarding H1N1 and its preventions measures such as wearing face-masks, washing hands and avoiding close contact with infected patients, some of them had some misconceptions about the infection, such as the infection might be transmitted by eating pork meat.Â

Development of Antiatherosclerotic Drugs on the basis of Natural Products Using Cell Model Approach

Atherosclerosis including its subclinical form is one of the key medical and social problems. At present, there is no therapy available for widespread use against subclinical atherosclerosis. The use of synthetic drugs for the prevention of arteriosclerosis in its early stages is not sufficient because of the limited indications for severe side effects and high cost of treatment. Obviously, effective antiatherosclerotic drugs based on natural products would be a preferred alternative. Simple cell-based models for testing different natural products have been developed and the ability of natural products to prevent intracellular lipid accumulation in primary cell culture was evaluated. This approach utilizing cell models allowed to test effects of such direct antiatherosclerotic therapy, analyzing the effects mimicking those which can occur “at the level” of arterial wall via the inhibition of intracellular lipid deposition. The data from the carried out clinical trials support a point of view that the identification of antiatherosclerotic activity of natural products might offer a great opportunity for the prevention and treatment of atherosclerotic disease, reducing cardiovascular morbidity and mortality

Incorporation and localisation of ganglioside GM3 in human intimal atherosclerotic lesions

AbstractImmunohistochemical examination showed that sections of intimal atherosclerotic plaques contained cells and cell clusters as well as areas of extracellular matrix specifically stained with antibodies against ganglioside GM3. No immunohistochemical staining was observed in areas bordering the plaques where there was no histological evidence of atherosclerosis. To determine whether the ganglioside GM3 deposits in the intimal plaques derived directly from plasma or were synthesised by intimal cells, intimal plaque and plasma LDL were assayed for ganglioside GM3 fatty acid composition. This assay showed that more than 50% of the fatty acids of GM3 isolated from both atherosclerotic and normal intima are either minor fatty acids or those absent from LDL GM3. We conclude that the GM3 deposits present in intimal plaque arise in intimal cells and do not derive from plasma LDL

Lipid Regulators during Atherogenesis : expression of LXR, PPAR, and SREBP mRNA in the Human Aorta

Transcription factors LXRs, PPARs, and SREBPs have been implicated in a multitude of physiological and pathological processes including atherogenesis. However, little is known about the regulation of these transcription factors at different stages of atherosclerosis progression. Quantitative real-time polymerase chain reaction (qRT-PCR) was used to compare the contents of mRNAs in pairs intact-injured aorta fragments taken from the same donors. Only minor changes in LXR?, LXR?, PPAR?, PPAR?, SREBP1, and SREBP2 mRNA levels were found in initial lesions as compared with intact non-diseased tissue. The contents of all mRNAs but SREBP2 mRNA were found to be progressively up-regulated in fatty streaks and fibrous lipoid plaques. These changes were only partially reproduced in cultured macrophages upon lipid loading. Wave-shaped changes in abundance of correlations between given group of mRNAs and 28 atherosclerosis-related mRNA species in the course of atherogenesis were observed. The impact of specific mRNA correlations on the total correlations also significantly varied between different lesion types. The study suggests that the extent and forms of LXR/PPAR/SREBP participation in intima functions vary nonlinear in individual fashion in atherogenesis. We speculate that the observed changes in mRNAs expression and coupling reflect shifts in lipid ligands availability and cellular composition in the course of atherosclerosis progression

Association of Mitochondrial Genetic Variation with Carotid Atherosclerosis

Peer reviewe

High expression of Cathepsin E in tissues but not blood of patients with Barrett’s esophagus and adenocarcinoma

Background Cathepsin E (CTSE), an aspartic proteinase, is differentially expressed in the metaplasia–dysplasia–neoplasia sequence of gastric and colon cancer. We evaluated CTSE in Barrett’s esophagus (BE) and cancer because increased CTSE levels are linked to improved survival in several cancers, and other cathepsins are up-regulated in BE and esophageal adenocarcinoma (EAC). Methods A total of 273 pretreatment tissues from 199 patients were analyzed [31 normal squamous esophagus (NE), 29 BE intestinal metaplasia, 31 BE with dysplasia (BE/D), 108 EAC]. CTSE relative mRNA expression was measured by real-time polymerase chain reaction, and protein expression was measured by immunohistochemistry. CTSE serum levels were determined by enzyme-linked immunosorbent assay. Results Median CTSE mRNA expression levels were ≥1,000-fold higher in BE/intestinal metaplasia and BE/D compared to NE. CTSE levels were significantly lower in EAC compared to BE/intestinal metaplasia and BE/D, but significantly higher than NE levels. A similar expression pattern was present in immunohistochemistry, with absent staining in NE, intense staining in intestinal metaplasia and dysplasia, and less intense EAC staining. CTSE serum analysis did not discriminate patient groups. In a uni- and multivariable Cox proportional hazards model, CTSE expression was not significantly associated with survival in patients with EAC, although CTSE expression above the 25th percentile was associated with a 41 % relative risk reduction for death (hazard ratio 0.59, 95 % confidence interval 0.27–1.26, p = 0.17). Conclusions CTSE mRNA expression is up-regulated more than any known gene in Barrett intestinal metaplasia and dysplasia tissues. Protein expression is similarly highly intense in intestinal metaplasia and dysplasia tissues