动脉粥样硬化中巨噬细胞介导胞葬作用的研究进展

动脉粥样硬化斑块内累积的大量凋亡和坏死细胞是斑块增大、坏死核心形成及斑块破裂的主要原因。生理状态下,机体通过巨噬细胞等吞噬细胞介导的胞葬作用能及时吞噬和清除凋亡细胞。然而近年来研究表明,斑块内凋亡细胞的清除速度远远低于生理状态,其机制与巨噬细胞介导的胞葬功能障碍密切相关。本文综述了巨噬细胞介导的胞葬作用及其功能缺陷在动脉粥样硬化中的研究进展,期望为动脉粥样硬化性心血管疾病防治提供理论和实验基础。     

Apoptosis in atherosclerosis: beneficial or detrimental?

Several groups have demonstrated apoptotic cell death in atherosclerotic plaques. The significance of apoptosis in atherosclerosis depends on the stage of the plaque, localization and the cell types involved. Both macrophages and smooth muscle cells undergo apoptosis in atherosclerotic plaques. Apoptosis of macrophages is mainly present in regions showing signs of DNA synthesis/repair. Smooth muscle cell apoptosis is mainly present in less cellular regions and is not associated with DNA synthesis/repair. Even in early stages of atherosclerosis smooth muscle cells become susceptible to undergoing apoptosis since they increase different pro-apoptotic factors. Moreover, recent data indicate that smooth muscle cells may be killed by activated macrophages. The loss of the smooth muscle cells can be detrimental for plaque stability since most of the interstitial collagen fibers, which are important for the tensile strength of the fibrous cap, are produced by SMC. Apoptosis of macrophages could be beneficial for plaque stability if apoptotic bodies are removed. Apoptotic cells that are not scavenged in the plaque activate thrombin which could further induce intraplaque thrombosis. It can be concluded that apoptosis in the primary atherosclerosis is detrimental since it could lead to plaque rupture and thrombosis. Recent data of our group indicate that apoptosis decreases after lipid lowering which could be important in our understanding of the cell biology of plaque stabilization.     

Exploring the role of extracellular matrix proteins to develop biomarkers of plaque vulnerability and outcome

Cardiovascular disease (CVD) is the most common cause of death in industrialized countries. One underlying cause is atherosclerosis, which is a systemic disease characterized by plaques of retained lipids, inflammatory cells, apoptotic cells, calcium and extracellular matrix (ECM) proteins in the arterial wall. The biologic composition of an atherosclerotic plaque determines whether the plaque is more or less vulnerable, that is prone to rupture or erosion. Here, the ECM and tissue repair play an important role in plaque stability, vulnerability and progression. This review will focus on ECM remodelling in atherosclerotic plaques, with focus on how ECM biomarkers might predict plaque vulnerability and outcome.     

抗动脉粥样硬化的新靶点——CD47

动脉粥样硬化是一种发生于大中型动脉内膜的进行性病变,是导致心脑血管疾病的主要病理基础。目前对于动脉粥样硬化的治疗尚不能令人满意,寻找新的更为有效的治疗靶点是当今医学的一大热点。CD47作为一种广泛表达的蛋白,通过与其配体信号调节蛋白α或血小板反应蛋白1结合,可从多种途径促进动脉粥样硬化的发生发展,如:阻断凋亡细胞的胞葬过程,促进内皮细胞的凋亡,抑制一氧化氮的生理功能,增加细胞黏附因子的产生等。通过抑制CD47表达可以阻断这些途径,延缓甚至逆转动脉粥样硬化,因此CD47可能成为未来抗动脉粥样硬化研究中的重要靶点。     

Phenotypic High-Throughput Screening in Atherosclerosis Research: Focus on Macrophages

Atherosclerosis is a complex disease characterized by arterial lesions consisting of macrophage foam cells, smooth muscle cells, lymphocytes and other cell types. As atherosclerotic lesions mature, they can rupture and thereby trigger thrombosis that can result in tissue infarction. Macrophage foam cells develop in the subendothelial space when cells take up cholesterol from modified forms of low-density lipoprotein (LDL) and other apolipoprotein B-containing lipoproteins. Current therapies to limit atherosclerosis focus on altering the plasma lipid composition, most commonly by reducing circulating LDL levels. No current therapy is specifically designed to alter the cellular composition of atherosclerotic lesions. To address this deficit, phenotypic high-throughput drug screens have been developed to identify compounds that reduce the uptake of oxidized LDL by macrophages or to identify compounds that increase the efflux of cholesterol from macrophages. Additional phenotypic screens can be envisaged that address cellular processes in active atherosclerotic lesions including macrophage apoptosis and efferocytosis.     

树突状细胞在动脉粥样硬化中的作用

基础和临床研究均证实,炎症反应在动脉粥样硬化(atherosclerosis,AS)的发生、发展及其导致的临床事件过程中起着重要作用.在发生AS的血管内膜和粥样斑块中可见T淋巴细胞、巨噬细胞以及树突状细胞(dendritic cell,DC)聚集现象.作为激活T淋巴细胞最主要的抗原提呈细胞,DC具有决定T淋巴细胞活化、凋亡以及聚集等的重要功能.文章就DC与AS病变的相关性进行了综述.     

CD40-CD40L interactions in atherosclerosis.

Increasing evidence supports a central role for CD40-CD40L interactions in the pathogenesis of atherosclerosis. Recently, we have shown that CD40L deficiency as well as pharmacological inhibition of CD40L in ApoE(-/-) mice results in the development of a stable atherosclerotic plaque phenotype. This phenotype is rich in smooth muscle cells and collagen, and contains only a small amount of macrophages and T-lymphocytes. CD40 and CD40L protein are present in almost all cell types in human atherosclerotic lesions. Expression was observed in early plaques, but was more predominant in advanced, rupture-prone, and ruptured plaques. Because most of the acute complications of atherosclerosis are the result of plaque rupture, CD40L inhibition might be a novel therapeutic approach to prevent atherosclerotic plaque destabilization and plaque rupture.     

The macrophage at the crossroads of insulin resistance and atherosclerosis

The macrophage has emerged as an important player in the pathogenesis of both atherosclerosis and insulin resistance. Cross-talk between inflammatory macrophages and adipocytes may be involved in insulin resistance in peripheral tissues. Defective insulin signaling in cells of the arterial wall including macrophages may promote the development of atherosclerosis. Insulin resistant macrophages are more susceptible to endoplasmic reticulum stress and apoptosis in response to various stimuli such as nutrient deprivation, free cholesterol loading, and oxidized LDL. Increased apoptosis of insulin resistant macrophages and impaired phagocytic clearance of apoptotic cells by insulin resistant macrophages in atherosclerotic lesions may lead to enhanced postapoptotic necrosis, larger lipid-rich cores, increased inflammation, and more complex vulnerable plaques.     

基于单细胞转录组鉴定动脉粥样硬化自身免疫表征

[目的]基于单细胞转录组生物信息学方法探讨动脉粥样硬化免疫微环境特征,挖掘免疫炎症与动脉粥样硬化之间潜在的联系。[方法]从GEO数据库中提取单细胞转录组数据集GSE159677,可视化分析颈动脉粥样硬化斑块区及其近心端毗邻非斑块区细胞组成成分,利用CellChat整合细胞间通讯网络,分析细胞间交互作用差异,识别动脉粥样硬化斑块免疫炎症信号通路差异,探索动脉粥样硬化免疫微环境中细胞间受体-配体特异性变化通路。[结果]本研究从单细胞测序的视角分析了动脉粥样硬化斑块内的细胞构成和细胞通讯。研究发现,在动脉粥样硬化斑块的细胞构成中内皮细胞和平滑肌细胞减少,而T细胞、单核细胞、巨噬细胞及软骨细胞明显增加。通过细胞通讯分析,发现树突状细胞、单核细胞、巨噬细胞、自然杀伤细胞与内皮细胞间的通讯作用及部分细胞与单核细胞间的通讯作用均有显著的改变,相关信号通路包括CXCL家族与ACRK1、CCL家族与ACRK1、MIF与CD74等配体-受体互作。MIF、ANXA1、YNF、RETN、LGASL9等对单核细胞以及NAMPT、CCL2、TNFSF12对内皮细胞的通讯改变在免疫炎症反应调控动脉粥样硬化机制中起着...     

Pathogenic immunity in systemic lupus erythematosus and atherosclerosis: common mechanisms and possible targets for intervention

Systemic lupus erythematosus (SLE) is an autoimmune disorder that primarily affects young women and is characterized by inflammation in several organs including kidneys, skin, joints, blood and nervous system. Abnormal immune cellular and humoral responses play important roles in the development of the disease process. Impaired clearance of apoptotic material is a key factor contributing to the activation of self‐reactive immune cells. The incidence of atherosclerotic cardiovascular disease (CVD) is increased up to 50‐fold in patients with SLE compared to age‐ and gender‐matched controls, and this can only partly be explained by traditional risk factors for CVD. Currently, there is no effective treatment to prevent CVD complications in SLE. Traditional preventive CVD therapies have not been found to significantly lower the incidence of CVD in SLE; therefore, there is a need for novel treatment strategies and increased understanding of the mechanisms involved in the pathogenesis of CVD complications in SLE. The pathogenic immune responses in SLE and development of atherosclerotic plaques share some characteristics, such as impaired efferocytosis and skewed T‐cell activation, suggesting the possibility of identifying novel targets for intervention. As novel immune‐based therapies for CVD are being developed, it is possible that some of these may be effective for the prevention of CVD and for immunomodulation in SLE. However, further understanding of the mechanisms leading to an increased prevalence of cardiovascular events in SLE is critical for the development of such therapies.     

Endocytosed lysophosphatidylcholine, through the scavenger receptor, plays an essential role in oxidized low-density lipoprotein-induced macrophage proliferation

The growth of cellular components is one of the characteristic events in the development of atherosclerosis. It is generally accepted that smooth muscle cells proliferate in atherosclerotic lesions. It has recently become evident that macrophage-derived foam cells also proliferate in the early stage of the atherosclerotic lesions. Our recent reports have demonstrated induction of macrophage proliferation in vitro by oxidized low density lipoprotein (Ox-LDL), in which a transport of lysophosphatidylcholine into cells by efficient endocytic uptake of Ox-LDL through the scavenger receptor pathway is important. Because macrophage-derived foam cells play an important role in the development of the early atherosclerotic lesions, it seems reasonable to expect that the Ox-LDL-induced macrophage proliferation may be linked to atherosclerotic processes in vivo.     

Apoptosis,a major determinant of atherothrombosis

Clinical manifestations of atherosclerosis are the consequences of atherosclerotic plaque rupture which triggers thrombus formation. Tissue factor (TF) is a key element in the initiation of the coagulation cascade and is crucial in thrombus formation following plaque disruption. TF activity is highly dependent on the presence of phosphatidylserine (PS), an anionic phospholipid that is redistributed on the cell surface during apoptotic death conferring a potent procoagulant activity to the apoptotic cell. Apoptosis occurs in the human atherosclerotic plaque, and shed membrane apoptotic microparticles rich in PS are produced in considerable amounts within the lipid core. These microparticles carry almost all TF activity and are responsible for the procoagulant activity of the plaque. Moreover, luminal endothelial cell apoptosis might be responsible for thrombus formation on eroded plaques without rupture. Apoptosis might also play a major role in blood thrombogenicity via circulating procoagulant microparticles that are found at high levels in patients with acute coronary syndromes.     

Consequences and therapeutic implications of macrophage apoptosis in atherosclerosis: the importance of lesion stage and phagocytic efficiency

Macrophage apoptosis occurs throughout all stages of atherosclerosis, yet new findings in vivo suggest that the consequences of this event may be very different in early versus late atherosclerotic lesions. In early lesions, where phagocytic clearance of apoptotic cells appears to be efficient, macrophage apoptosis is associated with diminished lesion cellularity and decreased lesion progression. In late lesions, however, a number of factors may contribute to defective phagocytic clearance of apoptotic macrophages, leading to secondary necrosis of these cells and a proinflammatory response. The cumulative effect of these late lesional events is generation of the necrotic core, which, in concert with proatherogenic effects of residual surviving macrophages, promotes further inflammation, plaque instability, and thrombosis. Thus, the ability or lack thereof of lesional phagocytes to safely clear apoptotic macrophages may be an important determinant of acute atherothrombotic clinical events. Further understanding of the mechanisms involved in macrophage apoptosis and phagocytic clearance might lead to novel therapeutic strategies directed against the progression of advanced plaques.     

老年患者股动脉和颈动脉及冠状动脉粥样硬化斑块稳定性的比较

目的　探讨股动脉、颈动脉、冠状动脉粥样硬化斑块的稳定性。方法　收集我院老年尸体解剖病例 15例 ,将所有病例的两侧股动脉、两侧颈动脉、左冠状动脉前降支进行连续取材 ,常规病理检查 ,部分节段行α 平滑肌肌动蛋白、CD6 8、bax染色。结果　股动脉粥样硬化斑块中的平滑肌细胞、巨噬细胞数量与颈动脉相近。与冠状动脉比较 ,股动脉粥样硬化斑块中的平滑肌细胞相对多 ,巨噬细胞相对少 ;bax在巨噬细胞的表达多 ,在平滑肌细胞的表达少。结论　平滑肌细胞、巨噬细胞数量的不同导致了 3种动脉粥样硬化斑块不同的稳定性。股动脉中的粥样硬化斑块较冠状动脉更稳定。     

Apoptosis and angiogenesis are induced in the unstable coronary atherosclerotic plaque

OBJECTIVE: Apoptosis and angiogenesis may be involved in the pathogenesis of atherosclerosis and plaque destabilization. In this study, we investigated if apoptosis and angiogenesis were induced in the unstable human coronary atherosclerotic plaque compared to stable atherosclerotic plaque. METHODS: Atherosclerotic plaques from patients with stable (n = 9) and unstable angina (n = 13) were obtained by directional coronary atherectomy performed during percutaneous transluminal coronary angioplasty. Apoptosis was detected by terminal deoxynucleotidyl transferase end labelling (TUNEL), as well as by immunostaining for caspase 3, Bax and Bcl-2. Neovascularization was determined by immunostaining for the endothelial cell-specific CD31, vascular endothelial growth factor (VEGF-A), angiopoietin-1 (Ang-1), angiopoietin-2 (Ang-2), hypoxia inducible factor-1alpha (HIF-alpha), and the sections were quantified blindly. RESULTS: The apoptotic nuclei were more frequently found in the unstable coronary atherosclerotic plaques. When the number of apoptotic cells was quantified, an increased apoptotic index was found in the unstable plaques (P = 0.04). The positive staining for caspase-3 was increased in the unstable plaques (P = 0.0008), while no difference in either Bax or Bcl-2 was found between groups. Neovascularization, as evidenced by lumens surrounded by a CD31 positive endothelial layer, was more frequently present in the plaques from patients with unstable angina (P = 0.04). The number of cells with positive staining for VEGF-A was increased in unstable plaques (P = 0.005). No difference of Ang I, Ang II, HIF1-alpha was found between groups. CONCLUSIONS: In unstable human coronary plaques, apoptosis probably involving caspase 3 was found. The plaques had an increased neovascularization, probably induced by VEGF-A. These factors may contribute to explaining plaque destabilization and intraplaque haemorrhage.     

脂蛋白相关磷脂酶A2:一种独立血管风险预测因子和治疗新靶点

脂蛋白相关磷脂酶A2(lipoprotein-associated phospholipase A2,Lp-PLA2)可快速水解氧化低密度脂蛋白和脂蛋白(a)中的氧化磷脂分子,生成可溶性促炎和促凋亡介质-溶血卵磷脂和氧化游离脂肪酸,刺激单核巨噬细胞系统聚集和激活,诱导细胞凋亡和破坏死亡细胞的清除,在动脉粥样硬化脂质坏死核心的发展中起重要作用.Lp-PLA2不仅是冠状动脉疾病和缺血性卒中的独立风险标志物,而且在动脉粥样硬化斑块进展中起重要作用.选择性Lp-PLA2抑制剂可减少坏死核心的发展,可能对动脉粥样斑块起稳定作用,同时可能代表着一种动脉粥样硬化的治疗新靶点.     

脂蛋白相关磷脂酶A2:一种独立血管风险预测因子和治疗新靶点

脂蛋白相关磷脂酶A2(lipoprotein-associated phospholipase A2,Lp-PLA2)可快速水解氧化低密度脂蛋白和脂蛋白(a)中的氧化磷脂分子,生成可溶性促炎和促凋亡介质-溶血卵磷脂和氧化游离脂肪酸,刺激单核巨噬细胞系统聚集和激活,诱导细胞凋亡和破坏死亡细胞的清除,在动脉粥样硬化脂质坏死核心的发展中起重要作用.Lp-PLA2不仅是冠状动脉疾病和缺血性卒中的独立风险标志物,而且在动脉粥样硬化斑块进展中起重要作用.选择性Lp-PLA2抑制剂可减少坏死核心的发展,可能对动脉粥样斑块起稳定作用,同时可能代表着一种动脉粥样硬化的治疗新靶点.     

异鼠李素通过抑制泡沫细胞形成增加动脉粥样硬化斑块稳定性的机制研究

背景 泡沫细胞的形成是动脉粥样硬化重要的病理基础,其是由巨噬细胞吞噬大量胆固醇和三酰甘油后转化而来.因此,如何促进巨噬细胞的脂质代谢、抑制其转化为泡沫细胞是延缓动脉粥样硬化病情进展的关键.目的 分析异鼠李素通过抑制泡沫细胞形成增加动脉粥样硬化斑块稳定性的机制.方法 本实验时间为2020年8月至2021年10月.动物实验...     

Monocyte chemoattractant protein-1 in acute coronary syndromes: complex vicious interaction

Monocyte chemoattractant protein-1 (MCP-1) plays a crucial role both in the initiation and progression of atherosclerosis. MCP-1 is a unique cytokine produced by macrophages, smooth muscle cells and endothelial cells within atherosclerotic plaques and seems to be a reliable indicator of atherosclerotic plaque burden. Higher levels of MCP-1 have been associated with a poor prognosis and increased risk for death independent of other risk factors in patients with acute coronary syndromes. In this paper, we discussed the role of MCP-1 in the pathogenesis of acute coronary syndromes.     

Burying the dead: the impact of failed apoptotic cell removal (efferocytosis) on chronic inflammatory lung disease

Apoptosis and the removal of apoptotic cells (termed efferocytosis) are tightly coupled with the regulation of normal lung structure, both in the developing and adult organism. Processes that disrupt or uncouple this balance have the potential to alter normal cell turnover, ultimately resulting in the induction of lung pathology and disease. Apoptotic cells are increased in several chronic inflammatory lung diseases, including cystic fibrosis (CF), non-CF bronchiectasis, COPD, and asthma. While this may well be due to the enhanced induction of apoptosis, increasing data suggest that the clearance of dying cells is also impaired. Because efferocytosis appears to be a key regulatory checkpoint for the innate immune system, the adaptive immune system, and cell proliferation, the failure of this highly conserved process may contribute to disease pathogenesis by impeding both the resolution of inflammation and the maintenance of alveolar integrity. The recognition of impaired efferocytosis as a contributor to chronic inflammation may ultimately direct us toward the identification of new disease biomarkers, as well as novel therapeutic approaches.