Role of Cell Adhesion Molecules and Immune-Cell Migration in the Initiation,Onset and Development of Atherosclerosis

Atherosclerosis is currently the leading factor of death in developed countries. It is now recognized as a chronic immune-inflammatory disease, whose initial stages involve the interaction of leukocytes with the endothelial monolayer. The initial stage of atherosclerosis requires the interplay of various cell adhesion molecules and immune cells to trigger leukocyte and lymphocyte migration from the circulating blood into the arterial intima. Studies have unveiled the role of inflammatory mediators in the initiation, onset and progression of the disease. During the last few years we have gained a greater understanding of the mechanism that modulates monocyte, macrophage and T cell infiltration, the role these cells play in the atherosclerotic lesion, in the formation of the fibrous plaque formation with the consequent narrowing of the arteries and the mechanisms that lead to plaque rupture and the formation of thrombi and emboli. This review talks about the leukocyte recruitment in early atherosclerosis, the formation of the plaque, and the mechanisms that lead to thrombosis in advanced atherosclerosis. Finally, we discuss the potential for novel therapies to treat this disease.Key Words: CAMs, leukocyte, lymphocyte, migration, atherosclerosis, extravasation     

Scavenger receptor regulation and atherosclerosis

Atherosclerosis and its complications, such as coronary heart disease, heart infarction and stroke, are the leading causes of death in the developed world. High blood pressure, diabetes, smoking and a diet high in cholesterol and lipids clearly increase the likelihood of premature atherosclerosis, albeit other factors, such as the individual genetic makeup, may play an additional role. During atherosclerosis, uncontrolled cholesterol and lipid accumulation in macrophages and smooth muscle cells leads to foam cell formation and to the progression of the atherosclerotic plaque. This review will focus on foam cell formation within the atherosclerotic lesion, the involvement of the scavenger receptor genes in this process, and the possibility to interfere with scavenger receptor function to reduce the progression of atherosclerosis. To date, the regulatory mechanisms for the expression of scavenger receptor genes and their role in atherosclerosis are not well characterized. Knowledge on this subject could lead to a better understanding of the process, prevention and therapy of this disease.     

Lipid homeostasis and the formation of macrophage-derived foam cells in atherosclerosis

Atherosclerosis is a chronic, inflammatory disorder characterized by the deposition of excess lipids in the arterial intima. The formation of macrophage-derived foam cells in a plaque is a hallmark of the development of atherosclerosis. Lipid homeostasis, especially cholesterol homeostasis, plays a crucial role during the formation of foam cells. Recently, lipid droplet-associated proteins, including PAT and CIDE family proteins, have been shown to control the development of atherosclerosis by regulating the formation, growth, stabilization and functions of lipid droplets in macrophage-derived foam cells. This review focuses on the potential mechanisms of formation of macrophage-derived foam cells in atherosclerosis with particular emphasis on the role of lipid homeostasis and lipid droplet-associated proteins. Understanding the process of foam cell formation will aid in the future discovery of novel therapeutic interventions for atherosclerosis.     

Platelets: Pleiotropic roles in atherogenesis and atherothrombosis

Platelets are small, anucleate blood elements of critical importance in cardiovascular disease. The ability of platelets to activate and aggregate to form blood clots in response to endothelial injury, such as plaque rupture, is well established. These cells are therefore important contributors to ischaemia in atherothrombosis, and antiplatelet therapy is effective for this reason. However, growing evidence suggests that platelets are also important mediators of inflammation and play a central role in atherogenesis itself. Interactions between activated platelets, leukocytes and endothelial cells trigger autocrine and paracrine activation signals, resulting in leukocyte recruitment at and into the vascular wall. Direct physical interaction may contribute also, through platelet adhesion molecules assisting localization of monocytes to the site of atherogenesis and platelet granule release contributing to the chronic inflammatory milieu which leads to foam cell development and accelerated atherogenesis. Recent studies have shown that antiplatelet therapy in animal models of accelerated atherogenesis can lead to decreased plaque size and improve plaque stability. This review examines the complexity of platelet function and the nature of interactions between activated platelets, leukocytes and endothelial cells. We focus on the growing body of evidence that platelets play a critical role in atherogenesis and contribute to progression of atherosclerosis.     

Inflammation in atherosclerosis: a cause or a result of vascular disorders?

Sound data support the concept that in atherosclerosis, inflammation and dyslipidemia intersect each other and that irrespective of the initiator, both participate from the early stages to the ultimate fate of the atheromatous plaque. The two partakers manoeuvre a vicious circle in atheroma formation: dyslipidaemia triggers an inflammatory process and inflammation elicits dyslipidaemia. Independent of the initial cause, the atherosclerotic lesions occur focally, in particular arterial-susceptible sites, by a process that, although continuous, can be arbitrarily divided into a sequence of consecutive stages that lead from fatty streak to the fibro-lipid plaque and ultimately to plaque rupture and thrombosis. In the process, the initial event is a change in endothelial cells (EC) constitutive properties. Then, the molecular alarm signals send by dysfunctional EC are decoded by specific blood immune cells (monocytes, T lymphocytes, neutrophils, mast cells) and by the resident vascular cells, that respond by initiating a robust inflammatory process, in which the cells and the factors they secrete hasten the atheroma development. Direct and indirect crosstalk between the cells housed within the nascent plaque, complemented by the increase in risk factors of atherosclerosis lead to atheroma development and outcome. The initial inflammatory response can be regarded as a defense/protective reaction mechanism, but its further amplification, speeds up atherosclerosis. In this review, we provide an overview on the role of inflammation and dyslipidaemia and their intersection in atherogenesis. The data may add to the foundation of a novel attitude in the diagnosis and treatment of atherosclerosis.     

The multifaceted contributions of leukocyte subsets to atherosclerosis: lessons from mouse models

Chronic inflammation drives the development of atherosclerosis, and details regarding the involvement of different leukocyte subpopulations in the pathology of this disease have recently emerged. This Review highlights the surprising contribution of granulocyte subsets and mast cells to early atherogenesis and subsequent plaque instability, and describes the complex, double-edged role of monocyte, macrophage and dendritic-cell subsets through crosstalk with T cells and vascular progenitor cells. Improved understanding of the selective contributions of specific cell types to atherogenesis will pave the way for new targeted approaches to therapy.     

Postprandial lipoproteins and the molecular regulation of vascular homeostasis

Blood levels of triglyceride-rich lipoproteins (TRL) increase postprandially, and a delay in their clearance results in postprandial hyperlipidemia, an important risk factor in atherosclerosis development. Atherosclerosis is a multifactorial inflammatory disease, and its initiation involves endothelial dysfunction, invasion of the artery wall by leukocytes and subsequent formation of foam cells. TRL are implicated in several of these inflammatory processes, including the formation of damaging free radicals, leukocyte activation, endothelial dysfunction and foam cell formation. Recent studies have provided insights into the mechanisms of uptake and the signal transduction pathways mediating the interactions of TRL with leukocytes and vascular cells, and how they are modified by dietary lipids. Multiple receptor and non-receptor mediated pathways function in macrophage uptake of TRL. TRL also induce expression of adhesion molecules, cyclooxygenase-2 and heme-oxygenase-1 in endothelial cells, and activate intracellular signaling pathways involving mitogen-activated protein kinases, NF-κB and Nrf2. Many of these effects are strongly influenced by dietary components carried in TRL. There is extensive evidence indicating that raised postprandial TRL levels are a risk factor for atherosclerosis, but the molecular mechanisms involved are only now becoming appreciated. Here, we review current understanding of the mechanisms by which TRL influence vascular cell function.     

肥大细胞在动脉粥样硬化形成中的作用

动脉粥样硬化,是冠心病的病理基础,被认为是一种慢性炎症性疾病,涉及如巨噬细胞和T淋巴细胞等许多炎性细胞。肥大细胞是一种重要的免疫细胞,其功能主要是在超敏反应方面的作用。有病理学研究表明：肥大细胞在动脉粥样硬化斑块周围表达增加,这表明肥大细胞可能与疾病的进展有关。最近的研究表明,肥大细胞在动脉粥样硬化中确实起着重要的作用。本文通过总结肥大细胞在动脉粥样硬化形成中的作用,为在疾病进程中,通过调节肥大细胞功能来改善动脉粥样硬化的这种治疗方式的可能性提供依据。     

Molecular mechanisms of cholesterol or homocysteine effect in the development of atherosclerosis: Role of vitamin E

The development of atherosclerosis is a multifactorial process in which both elevated plasma cholesterol levels and proliferation of smooth muscle cells play a central role. Numerous studies have suggested the involvement of oxidative processes in the pathogenesis of atherosclerosis and especially of oxidized low density lipoprotein. Some epidemiological studies have shown an association between high dietary intake and high serum concentrations of vitamin E and lower rates of ischemic heart disease. Cell culture studies have shown that alpha-tocopherol brings about inhibition of smooth muscle cell proliferation. This takes place via inhibition of protein kinase C activity. alpha-Tocopherol also inhibits low density lipoprotein induced smooth muscle cell proliferation and protein kinase C activity. The following animal studies showed that vitamin E protects development of cholesterol induced atherosclerosis by inhibiting protein kinase C activity in smooth muscle cells in vivo. Elevated plasma levels of homocysteine have been identified as an important and independent risk factor for cerebral, coronary and peripheral atherosclerosis. However the mechanisms by which homocysteine promotes atherosclerotic plaque formation are not clearly defined. Earlier reports have been suggested that homocysteine exert its effect via H2O2 produced during its metabolism. To evaluate the contribution of homocysteine in the pathogenesis of vascular diseases, we examined whether the homocysteine effect on vascular smooth muscle cell growth is mediated by H2O2. We show that homocysteine induces DNA synthesis and proliferation of vascular smooth muscle cells in the presence of peroxide scavenging enzyme, catalase. Our data suggest that homocysteine induces smooth muscle cell growth through the activation of an H2O2 independent pathway and accelerate the progression of atherosclerosis. The results indicate a cellular mechanism for the atherogenicity of cholesterol or homocysteine and protective role of vitamin E in the development of atherosclerosis.     

一个日益重要的冠心病标志物———新蝶呤

动脉粥样硬化是一种慢性炎症过程,炎症反应在动脉粥样斑块的形成、发展、稳定性丧失和斑块破裂过程中都起着非常重要的作用,贯穿于动脉粥样硬化的各个环节。从早期的脂质条纹到进一步的动脉粥样病变及血栓性并发症都能见到炎症细胞的浸润,其中又以激活的巨噬细胞尤为重要。新蝶呤是巨噬细胞激活后的代谢产物,它不仅是巨噬细胞激活的炎症标志物,还参与多种调节氧化平衡的生化途径,增加氧化应激水平,促进动脉粥样硬化的进展,是斑块不稳定性及不良性心血管事件的独立预测因子。在临床上,降低血清新蝶呤水平可以降低冠心病患者发生危险事件的风险。因此,新蝶呤对冠心病的诊断和治疗都有重要意义。本文将对新蝶呤在冠心病中的角色做一综述。     

Enzymology and molecular biology of prokaryotic sulfite oxidation

The intracellular bacterial pathogen Chlamydia pneumoniae causes respiratory tract infection and has been associated with atherosclerosis and coronary artery disease. Since atherosclerosis is a progressive disease and is considered to be a chronic inflammation of the artery vessel wall, the interaction of C. pneumoniae with cells of the vasculature that can result in a local inflammatory response is of paramount importance. In this essay we review the pathophysiology of atherosclerosis in the context of C. pneumoniae infection and present an integrated model that includes the involvement of C. pneumoniae in all stages of atherogenesis including initiation, inflammation, fibrous plaque formation, plaque rupture and thrombosis. We hypothesize that acute and persistent infection of professional immune cells (T-cells, monocytes and macrophages) and non-immune cells (endothelial cells and smooth muscle cells) contributes to a sustained inflammatory response mediated by extensive cellular 'crosstalk' and numerous cytokines/chemokines. This cascade of inflammatory mediators may contribute to cellular dysfunction and tissue remodelling of the arterial intima. An improved understanding of the precise mechanism(s) of C. pneumoniae involvement in atherogenesis may help resolve the question of causality however, at the present time, we interpret the data as favoring a contributory rather than a causal role. Future research directed at the discovery of chlamydial virulence factors necessary for intracellular survival and subsequent alterations in host cell gene expression including signalling pathways may be important for the design of future clinical trials.     

Induction of antioxidant stress proteins in vascular endothelial and smooth muscle cells: protective action of vitamin C against atherogenic lipoproteins.

Elevated levels of lipid peroxidation and increased formation of reactive oxygen species within the vascular wall in atherosclerosis can overwhelm cellular antioxidant defence mechanisms. Accumulating evidence implicates oxidatively modified low density lipoproteins (LDL) in vascular dysfunction in atherosclerosis and oxidized LDL have been localized with in atherosclerotic lesions. We here report that human oxidatively modified LDL induce expression of 'antioxidant-like' stress proteins in vascular cells, involving increases in the activity of L-cystine transport, glutathione synthesis, heme oxygenase-1 and the murine stress protein MSP23. Moreover, treatment of human arterial smooth muscle cells with the dietary antioxidant vitamin C markedly attenuates adaptive increases in endogenous antioxidant gene expression and affords protection against smooth muscle cell apoptosis induced by moderately oxidized LDL. As vascular cell death is a key feature of atherosclerotic lesions and may contribute to the plaque 'necrotic' core, cap rupture and thrombosis, our findings suggest that the cytoprotective actions of vitamin C could limit plaque instability in advanced atherosclerosis.     

Smooth muscle cell phenotypes in atherosclerotic lesions

Recently, there has been a dramatic change in the way we think about the role of vascular smooth muscle cells in atherosclerosis, and it is now generally accepted that a dearth of vascular smooth muscle cells in an atherosclerotic plaque is a detrimental feature of the disease. Indeed, it is now recognized that the phenotypes of vascular smooth muscle cells within a plaque dictate its features, progression and stability. Therefore an understanding of the processes that generate and regulate vascular smooth muscle cell heterogeneity are of critical importance for future therapeutic advancement in the treatment of atherosclerosis.     

Th17细胞和Treg细胞与动脉粥样硬化

动脉粥样硬化从脂质条纹的形成到更复杂的病变和斑块破裂的进程是由多种不同类型的细胞和细胞因子网络共同参与作用的,其中最主要的是Th17细胞和Treg细胞及它们分泌的细胞因子。大量研究显示,Th17细胞对动脉粥样硬化的作用仍存在争议,但大部分研究仍认为其具有促动脉粥样硬化的作用。Treg细胞具有抗动脉粥样硬化的作用,Th17／Treg平衡对动脉粥样硬化的发生和发展具有重要的调节作用。本文将对Th17细胞、Treg细胞的生物学特性以及Th17细胞、Treg细胞和Th17／Treg平衡对动脉粥样硬化影响的最新研究进展做一综述。     

Role of AGEs in the progression and regression of atherosclerotic plaques

The formation of advanced glycation end-products(AGEs) is an important cause of metabolic memory in diabetic patients and a key factor in the formation of atherosclerosis(AS) plaques in patients with diabetes mellitus. Related studies showed that AGEs could disrupt hemodynamic steady-state and destroy vascular wall integrity through the endothelial barrier damage, foam cell(FC) formation, apoptosis, calcium deposition and other aspects. At the same time, AGEs could initiate oxidative stress and inflammatory response cascade via receptor-depended and non-receptor-dependent pathways, promoting plaques to develop from a steady state to a vulnerable state and eventually tend to rupture and thrombosis. Numerous studies have confirmed that these pathological processes mentioned above could lead to acute coronary heart disease(CHD) and other acute cardiovascular and cerebrovascular events. However, the specific role of AGEs in the progression and regression of AS plaques has not yet been fully elucidated. In this paper, the formation, source, metabolism, physical and chemical properties of AGEs and their role in the migration of FCs and plaque calcification are briefly described, we hope to provide new ideas for the researchers that struggling in this field.     

A critical function of Th17 proinflammatory cells in the development of atherosclerotic plaque in mice

Considerable evidence supports that the CD4(+) T cell-mediated immune response contributes to the development of atherosclerotic plaque. However, the effects of Th17 cells on atherosclerosis are not thoroughly understood. In this study, we evaluated the production and function of Th17 and Th1 cells in atherosclerotic-susceptible ApoE(-/-) mice. We observed that the proportion of Th17 cells, as well as Th1, increased in atherosclerotic ApoE(-/-) mice compared with nonatherosclerotic wild-type littermates. In ApoE(-/-) mice with atherosclerosis, the expression of IL-17 and retinoic acid-related orphan receptor γt was substantially higher in the arterial wall with plaque than in the arterial wall without plaque. Increased Th17 cells were associated with the magnitude of atherosclerotic plaque in ApoE(-/-) mice. Importantly, treatment of ApoE(-/-) mice with neutralizing anti-IL-17 Ab dramatically inhibited the development of atherosclerotic plaque, whereas rIL-17 application significantly promoted the formation of atherosclerotic plaque. These data demonstrate that Th17 cells play a critical role in atherosclerotic plaque formation in mice, which may have implications in patients with atherosclerosis.     

Induction of antioxidant stress proteins in vascular endothelial and smooth muscle cells: Protective action of vitamin C against atherogenic lipoproteins

Elevated levels of lipid peroxidation and increased formation of reactive oxygen species within the vascular wall in atherosclerosis can overwhelm cellular antioxidant defence mechanisms. Accumulating evidence implicates oxidatively modified low density lipoproteins (LDL) in vascular dysfunction in atherosclerosis and oxidized LDL have been localized with in atherosclerotic lesions. We here report that human oxidatively modified LDL induce expression of ‘antioxidant-like’ stress proteins in vascular cells, involving increases in the activity of l-cystine transport, glutathione synthesis, heme oxygenase-1 and the murine stress protein MSP23. Moreover, treatment of human arterial smooth muscle cells with the dietary antioxidant vitamin C markedly attenuates adaptive increases in endogenous antioxidant gene expression and affords protection against smooth muscle cell apoptosis induced by moderately oxidized LDL. As vascular cell death is a key feature of atherosclerotic lesions and may contribute to the plaque ‘necrotic’ core, cap rupture and thrombosis, our findings suggest that the cytoprotective actions of vitamin C could limit plaque instability in advanced atherosclerosis.     

Mechanisms of leukocyte recruitment to atherosclerotic lesions: future prospects

PURPOSE OF REVIEW: Leukocyte invasion in the arterial wall is critical in the development of atherosclerotic lesions. This review describes recent advances in the understanding of leukocyte recruitment in atherogenesis and in the development of vulnerable plaque. It also discusses limitations in the current knowledge of this process and how these limitations may be addressed. RECENT FINDINGS: The adhesive function of platelets has recently been highlighted as an important recruitment mechanism in atherosclerosis. For example, targeted deficiency of P-selectin in platelets reduces atherosclerosis in mice. Platelets also increase monocyte recruitment in atherosclerosis by secreting chemokines such as platelet factor 4 (CXCL4) or RANTES (CCL5), which trigger monocyte arrest in atherosclerotic arteries. A causal role for RANTES in atherosclerosis was shown by a protective effect of the blockage of RANTES receptors in apolipoprotein E-deficient mice. A similar effect was also demonstrated for the fractalkine receptor CX3CR1. Moreover, the classic chemoattractant LTB4 plays important roles in atherosclerosis, inasmuch as the absence of the principal LTB4 receptor (BLT1) reduces early atherosclerosis in mice. Novel data have also shown that many types of cells in lesions express 5-lipoxygenase, which indicates a rich source of leukotrienes in plaque. SUMMARY: Recent data provide evidence for the involvement of several adhesive and signalling mechanisms in leukocyte recruitment in atherosclerosis. However, the specific mechanisms that are responsible for the accumulation of proatherogenic leukocytes in lesions are unclear. Detailed study of certain subclasses of leukocytes in the recruitment process will be important in future studies in this field.     

固有免疫应答与动脉粥样硬化关系的研究进展

固有免疫应答在动脉粥样硬化(atherosclerosis,As)的发生和发展中起重要作用．固有免疫应答细胞,包括单核/巨噬细胞、肥大细胞、自然杀伤细胞、中性粒细胞和树突状细胞,是机体抵御微生物和异物入侵的第一道防线．这些细胞广泛参与As中泡沫细胞形成、斑块内基质降解、细胞凋亡、血管新生和斑块破裂等事件．模式识别受体是免疫细胞上识别病原体(或某些内源性成分)相关分子模式的一类受体分子,包括Toll样受体和NOD样受体,介导固有免疫应答反应．Toll样受体在固有免疫应答细胞中具有不同程度的表达,在As中具有不同的作用,如TLR2和TLR4对As起促进作用,而TLR3具有As保护作用．NLRP3炎性体与动脉血管壁的早期损伤有关．对固有免疫应答细胞及模式识别受体在As形成中的作用进行深入研究,不仅有助于理解As的形成过程,而且还能为临床上防治心血管类疾病提供了新的治疗靶点和诊断指标．