ISSN:0957-9672    

出版商:OVID    

年代:2001

数据来源: OVID

摘要:

Chondroitin sulfate proteoglycans (CSPGs) of the arterial wall are generally considered to be atherogenic because of their ability to trap cholesterol-rich lipoproteinsin vitro. Nevertheless, CSPGs are a diverse group of molecules with a long evolutionary history and distinct biologic functions. The three principal CSPGs in the arterial wall are versican, which is part of the hyalectan gene family; and decorin and biglycan, which are members of a separate gene family, the small leucine-rich proteoglycans. Importantly, there is now substantial evidence that the different molecular species of CSPGs participate unequally in lipoprotein retention, and that they exert unequal regulatory effects that are related to atherogenesis. Recently available murine models with genetic manipulations that affect CSPGs now allow causal studies of the roles of these molecules to be conductedin vivo, with occasionally surprising results. Moreover, tools are being developed to examine human genetic variations that are relevant to CSPGs, which may provide additional important insights into the human disease. The era in which proteoglycans are regarded as a nondescript backdrop, playing purely nonspecific structural roles, is over. Studies in manipulated animals and in human populations will continue to reveal precise, dynamic roles for these fascinating and ancient molecules.

ISSN:0957-9672    

出版商:OVID    

年代:2001

数据来源: OVID

摘要:

The scope of this review is to discuss the new advances in our understanding of the role of scavenger receptor class A in the initiation and modulation of the atherosclerotic process. Through the approaches of gene manipulation in the mouse model, a substantial body of literature has accumulated that depicts scavenger receptor class A as a central player in atherogenesis. In studies of scavenger receptor class A overexpression in macrophages through bone marrow transplantation using transgenic donor material, recipient mice with hyperlipidemia caused either by apolipoprotein E or LDL receptor deficiency did not show convincing changes in the degree of atherosclerosis development compared with controls. Conversely, the deletion of the scavenger receptor class A gene in the mouse has shown, in a consistent and significant fashion, that this receptor serves a pro-atherogenic function under hyperlipidemic conditions, as both apolipoprotein E and LDL receptor-deficient mice had reduced atherosclerosis in the absence of scavenger receptor class A. In addition, we have recently shown that C57BL/6 mice are protected from diet-induced atherosclerosis when they lack scavenger receptor class A, and that the macrophage is the cell type responsible for the effect of scavenger receptor class A deficiency in reducing lesion formation in C57BL/6 and LDL receptor null mice. Together, these results demonstrate that macrophage scavenger receptor class A contributes significantly to atherosclerotic lesion formation, and suggest that the uptake of oxidized or modified lipoproteins by vessel wall macrophages is a central process in atherogenesis.

ISSN:0957-9672    

出版商:OVID    

年代:2001

数据来源: OVID

摘要:

The HDL receptor scavenger receptor class B type I plays an important role in meditating the uptake of HDL-derived cholesterol and cholesteryl ester in the liver and steroidogenic tissues. However, the mechanism by which scavenger receptor class B type I mediates selective cholesterol uptake is unclear. In hepatocytes scavenger receptor class B type I mediates the transcytosis of cholesterol into bile, appears to be expressed on both basolateral and apical membranes, and directly interacts with a PDZ domain containing protein that may modulate the activity of scavenger receptor class B type I. This suggests the involvement of scavenger receptor class B type I in higher order complexes in polarized cells. Scavenger receptor class B type I expression has been shown to alter plasma membrane cholesterol distribution and induce the formation of novel membrane structures, suggesting multiple roles for scavenger receptor class B type I in the cell. A close examination of scavenger receptor class B type I function in polarized cells may yield new insights into the mechanism of scavenger receptor class B type I-mediated HDL selective uptake and the effects of scavenger receptor class B type I on cellular cholesterol homeostasis.

ISSN:0957-9672    

出版商:OVID    

年代:2001

数据来源: OVID

摘要:

Men have an earlier onset and higher incidence of coronary heart disease than women, independent of environmental risk factor exposure. As a consequence, there has been considerable interest in the potential role of sex hormones in atherogenesis. An emerging body of evidence suggests that sex-specific tissue and cellular characteristics may mediate sex-specific responses to a variety of stimuli. Recent studies have shown that oestrogen, progesterone and androgens all regulate processes integral to human macrophage foam cell formation, a key event in atherogenesis, in a sex-specific manner; findings that may have important implications for understanding the sex gap in atherosclerosis. Physiological levels of 17β-estradiol and progesterone are both associated with a female-specific reduction in cholesteryl ester accumulation in human macrophages. By contrast, androgens increase cholesteryl ester formation in male but not in female donor human macrophages. This review summarizes current data concerning the sex-specific effects of sex hormones on processes important to macrophage foam cell formation and the basic mechanisms responsible for the sex specificity of such effects. Future research in this promising field may eventually lead to the novel concept of ‘sex-specific’ treatments directed at inhibiting atherogenesis.

ISSN:0957-9672    

出版商:OVID    

年代:2001

数据来源: OVID

摘要:

New insights into the endothelium as a dynamic, interactive organ have generated increased interest in endothelial cell transcriptional regulation. Peroxisomal proliferator-activated receptors (PPARs), as ligand-activated nuclear receptors expressed in endothelial cells, represent one important pathway that likely influences vascular responses both directly and indirectly by altering gene expression. PPAR ligands such as fibrates (PPAR-α) and insulin-sensitizing thiazolidinediones (PPAR-γ) are in clinical use and may alter the process of atherosclerosis. The present review highlights the emerging evidence for PPAR-α and PPAR-γ expression in the vasculature, as well as their potential roles in endothelial cell biology.

ISSN:0957-9672    

出版商:OVID    

年代:2001

数据来源: OVID

摘要:

Peroxisome proliferator-activated receptor (PPAR)-γ is a nuclear hormone receptor, with a well-established role in adipogenesis and glucose metabolism. Over the past 3 years several laboratories have reported that this protein can influence macrophage responses to a variety of inflammatory stimuli. The effect of PPAR-γ activation on macrophage lipid uptake, cholesterol efflux, and cytokine production have all recently been examined in several in-vitro culture systems. In addition, PPAR-γ ligands have been shown to influence atherosclerotic lesion formation in murine models of that disease. This review attempts to summarize and critically evaluate that work and its implications for the use of PPAR-γ activators in understanding and treating the pathogenetic processes that contribute to atherosclerotic plaque formation.

ISSN:0957-9672    

出版商:OVID    

年代:2001

数据来源: OVID

摘要:

The rationale for the present review is that oxysterols found in oxidized LDL (oxLDL) play a role in atherogenesis. This perspective is based on studies that show that induction of apoptosis in vascular cells is an important process in atherogenesis, that apoptosis can be induced by oxLDL, and that the oxysterol component of oxLDL is responsible for its proapoptotic activity. The evidence for these concepts is reviewed, as are studies on the mechanisms by which oxysterols can induce apoptosis. An elevation in intracellular calcium appears to be an early signal transduction event that leads to apoptosis through both the extrinsic and intrinsic apoptotic pathways.

ISSN:0957-9672    

出版商:OVID    

年代:2001

数据来源: OVID

摘要:

An increasing body of evidence from both animal models and human specimens suggests that apoptosis or programmed cell death is a major event in the pathophysiology of atherosclerosis. Although the significance of apoptosis in atherosclerosis remains unclear, it has been proposed that apoptotic cell death contributes to plaque instability, rupture and thrombus formation. Biochemical and genetic analyses of apoptosis provide an increasingly detailed picture of the intracellular signaling pathways involved. Nevertheless, it remains to be determined whether apoptosis can become a clinically important approach to modulate plaque progression. In this review, we have outlined some of the most recent results concerning apoptosis in atherosclerosis with a special focus on oxidized lipids, inflammation and therapeutic regulation of the apoptotic cell death process.

ISSN:0957-9672    

出版商:OVID    

年代:2001

数据来源: OVID

摘要:

Appreciation of the multifactorial nature of atherosclerosis requires a broad understanding of the mechanisms that underlie its pathogenesis. Autoimmune factors have recently been shown to be associated with the initiation and progression of atherosclerosis. In this context, modified lipoproteins were explored because of their de-novo occurrence within the vessel wall, and heat shock proteins are also being reported by several authors as triggers of autoimmune-like reactions that associate with atherosclerosis. Antiphospholipid antibodies in general and anti-β2-glycoprotein I (β2GPI) antibodies in particular have been shown to confer a procoagulant tendency in humans, either in the presence or the absence of the antiphospholipid syndrome. These findings and the ability of antibodies to β2GPI to activate monocytes and endothelial cells led us to consider whether they are proatherogenic. In a series of studies it was shown that inducing an immune response to β2GPI in atherosclerosis-prone mice accelerated atherosclerosis. We also demonstrated the abundance of β2GPI in the atheroma, in conjunction with immunopotent cells. Moreover, when β2GPI-reactive lymph node and spleen cells were transferred to LDL-receptor-deficient mice they promoted fatty streak formation, proving a direct proatherogenic role for β2GPI-specific lymphocytes. Perhaps the most important implications of the existence of antigen-specific immune reactions within the atheroma is the ability to exploit them for the purpose of selective immunomodulation. Indeed, we have found that inducing immunological tolerance to β2GPI by prior oral feeding with the antigen resulted in a significant reduction in the extent of atherosclerotic lesions. Thus, β2GPI is a candidate player in the atherosclerotic plaque, and can possibly be employed as an immunomodulator of plaque progression.

ISSN:0957-9672    

出版商:OVID    

年代:2001

数据来源: OVID