血小板参与动脉粥样硬化斑块形成的分子途径

血小板在血栓形成,血液凝固,维持血管稳态及修复血管损伤等生理病理过程中起重要作用。近年来研究发现血小板也可作为炎症细胞参与机体宿主防御,发挥免疫功能。动脉粥样硬化是一种慢性血管炎症性疾病,在血管炎症发生过程中,血小板可通过表面受体或释放储存在血小板颗粒中的分子促进血小板与炎症细胞(如血管内皮细胞、平滑肌细胞、单核细胞)相互作用,从而参与动脉粥样硬化发生。本文主要围绕血小板参与动脉粥样硬化斑块形成的途径,及其作为动脉粥样硬化早期防治靶点的最新进展进行综述。     

急性冠脉综合征长期抗栓治疗现状北大核心CSCD

血栓形成是急性冠脉综合征（ACS）病理生理机制中的重要环节和关键因素,血小板和凝血瀑布都参与到血栓的形成过程当中。当粥样硬化斑块破裂导致血栓形成时,血小板起主要作用,在动脉系统中形成白色血栓。而静脉系统的红色血栓常南血液瘀滞或炎症反应所触发,凝血瀑布在其形成过程中起到更重要的作用。     

OxLDL对动脉粥样硬化血栓作用研究的进展

动脉粥样硬化(AS)是心血管疾病的主要病理生理基础,也是导致心血管疾病死亡的主要病因.氧化低密度脂蛋白(oxLDL)在AS斑块的发生发展和AS血栓的形成中起重要作用.OxLDL及其组分通过多种途径直接或间接促进促凝血活动及AS血栓的形成.本文就oxLDL及其组分对促进血栓形成的相关细胞和通路的影响作一综述.     

急性冠脉综合征长期抗栓治疗现状

正血栓形成是急性冠脉综合征(ACS)病理生理机制中的重要环节和关键因素,血小板和凝血瀑布都参与到血栓的形成过程当中。当粥样硬化斑块破裂导致血栓形成时,血小板起主要作用,在动脉系统中形成白色血栓[1]。而静脉系统的红色血栓常由血液瘀滞或炎症反应所触发,凝血瀑布在其形成过程中起到更重要的作用[2]。在本文中,我们将在抗栓药物的作用、用法、时程等方面来阐述急性冠脉综合征患者的长期抗栓治疗现状。     

冠心病抗血小板治疗的进展(1)血小板在动脉粥样硬化形成和发展中的作用

长期以来人们对血小板在动脉粥样硬化中的作用认识不足,主要局限于凝血和血栓形成方面,因此使用抗血小板药物主要目的是为了防止血小板聚集和血栓形成,近年来的一些研究显示血小板作为"炎症细胞"其活化惑释放的一些炎症介质直接参与动脉粥样硬化的形成和发展,并且与斑块的不稳定关系密切,急性冠状动脉综合征(ACS)最主要的发病机制是斑块破裂后继发血栓形成,故ACS亦被称为动脉硬化血栓性疾病,而血小板是唯一的既作用于动脉粥样硬化的炎症反应又作用于血栓形成的细胞,因此不难理解为什么抗血小板治疗在ACS发病中起十分重要的作用,近年来循证医学研究(Cure试验、Credo试验)显示加强抗血小板治疗即阿司匹林 氯吡格雷可明显减少ACS患者心脏事件的发生率,再次证明抗血小板治疗在ACS发病中的重要地位.     

抗血小板药物的相互作用

动脉粥样硬化斑块破裂是激活血小板形成血栓,导致包括不稳定型心绞痛、心肌梗死、死亡等恶性心血管事件的始动因素。血小板在斑块破裂后血栓形成过程中起着关键作用,因此治疗中合理应用抗血小板药物非常重要。目前抗血小板治疗已是冠心病患者药物     

黏附分子细胞间黏附分子-1/E-选择素与冠心病

冠心病是一种高发病率和高病死率的疾病,炎症反应在冠状动脉粥样硬化斑块的形成中起着重要作用。活化的血管内皮细胞分泌的细胞黏附分子,如细胞间黏附分子-1和E-选择素等,它们介导内皮细胞与白细胞、血小板间的起始黏附,促进血液循环中白细胞、血小板黏附于血管内皮,引起炎症反应、血栓形成等,在动脉粥样硬化和冠心病的发生、发展中起重要作用。     

CD40-肿瘤坏死因子受体相关因子抑制剂在动脉粥样硬化治疗中的研究进展

CD40-CD40配体(CD40L)信号通路与动脉粥样硬化相关,在动脉粥样硬化起始、发展和并发症中起重要作用。CD40/CD40L是一对互补的跨膜糖蛋白,广泛表达于免疫细胞、内皮细胞、血小板、平滑肌细胞等,参与免疫、炎性反应、血栓形成等多种病理生理过程。动脉粥样硬化启动CD40的表达,激活下游信号通路,上调炎性反应和血栓形成相关基因的表达,阻断该信号通路是抗动脉粥样硬化的策略之一。     

氯吡格雷稳定易损斑块

动脉粥样硬化是缺血性卒中最重要的病因之一,而易损斑块在脑动脉粥样硬化性血栓形成中起重要作用。动脉粥样硬化是一个炎症过程,血小板的活化和聚集在其发生和发展以及斑块破裂后的血栓形成过程中起重要作用。因此,抗血小板治疗是预防卒中的重要手段。氯吡格雷和阿司匹林减少有症状颈动脉狭窄栓子(Clopidogrel and Aspirin forReduction of Emboli in Symptomatic Carotid Stenosis,CARESS)研究表明,氯吡格雷可有效稳定易损斑块,从而预防早期卒中。1动脉粥样硬化引起脑缺血的机制动脉粥样硬化好发于椎动脉、颈内动脉和小脑后下动脉。…     

靶向活化血小板的MRI显影可以在体内查出血栓形成和监察溶栓效果

血小板是血栓形成的关键，在动脉粥样硬化形成中起一定作用。作者评估用一种MRI显影剂[包括氧化铁微颗粒（MPIOs）和一种活化PⅡb／Ⅲa配体-引发结合部位（LIBS）的单链抗体]作颈动脉血栓和动脉粥样斑块影像。     

Novel targets for antithrombotic drug discovery

Platelet aggregation is a dynamic entity, capable of directing its own growth and stability via the activation of signaling cascades that lead to the expression and secretion of various secondary agonists. Recent data using proteomics and genomics strategies have established that signaling pathways during platelet aggregation are triggered by two homophilic adhesion molecules, CD84 and CD150 (SLAM), and by a novel EGF-containing receptor, PEAR1, which are tyrosine-phosphorylated in a platelet-aggregation-dependent fashion (N. Nanda, P. Andre, M. Bao et al., Platelet aggregation induces platelet aggregate stability via SLAM family receptor signaling, Blood 106 (2005) 3028-3034, N. Nanda, M. Bao, H. Lin et al., Platelet Endothelial Aggregation Receptor 1 (PEAR1), a novel epidermal growth factor repeat-containing transmembrane receptor, participates in platelet contact-induced activation, J. Biol. Chem. 280 (2005) 24680-24689). Analysis of SLAM-deficient mice revealed an overall defect in platelet aggregation in vitro and a delayed arterial thrombotic process in vivo. The data indicate that these aggregation co-receptors may function in a "platelet synapse" and may be novel targets for antithrombotic drug discovery.     

From the Cover: Slitrks control excitatory and inhibitory synapse formation with LAR receptor protein tyrosine phosphatases

The balance between excitatory and inhibitory synaptic inputs, which is governed by multiple synapse organizers, controls neural circuit functions and behaviors. Slit- and Trk-like proteins (Slitrks) are a family of synapse organizers, whose emerging synaptic roles are incompletely understood. Here, we report that Slitrks are enriched in postsynaptic densities in rat brains. Overexpression of Slitrks promoted synapse formation, whereas RNAi-mediated knockdown of Slitrks decreased synapse density. Intriguingly, Slitrks were required for both excitatory and inhibitory synapse formation in an isoform-dependent manner. Moreover, Slitrks required distinct members of the leukocyte antigen-related receptor protein tyrosine phosphatase (LAR-RPTP) family to trigger synapse formation. Protein tyrosine phosphatase σ (PTPσ), in particular, was specifically required for excitatory synaptic differentiation by Slitrks, whereas PTPδ was necessary for inhibitory synapse differentiation. Taken together, these data suggest that combinatorial interactions of Slitrks with LAR-RPTP family members maintain synapse formation to coordinate excitatory–inhibitory balance.     

Feedforward lateral inhibition in retinal bipolar cells: input-output relation of the horizontal cell-depolarizing bipolar cell synapse.

Lateral inhibition is the ubiquitous strategy used by visual neurons for spatial resolution throughout the animal kingdom. It has been a puzzle whether lateral inputs in retinal bipolar cells are mediated by the horizontal cell (HC)-cone feedback synapse, by the HC-bipolar cell feedforward synapse, or by both. By blocking the central inputs of the depolarizing bipolar cells (DBCs) with L-2-amino-4-phosphonobutyrate, we were able to eliminate the contribution of the feedback synapse and to demonstrate the postsynaptic light response in DBCs mediated by the HC-DBC feedforward synapse. The HC-DBC feedforward synapse contributes roughly one-third of the surround response whereas the HC-cone-DBC feedback synapse probably contributes the rest.     

Recruitment of dynein to the Jurkat immunological synapse

Binding of T cells to antigen-presenting cells leads to the formation of the immunological synapse, translocation of the microtubule-organizing center (MTOC) to the synapse, and focused secretion of effector molecules. Here, we show that upon activation of Jurkat cells microtubules project from the MTOC to a ring of the scaffolding protein ADAP, localized at the synapse. Loss of ADAP, but not lymphocyte function-associated antigen 1, leads to a severe defect in MTOC polarization at the immunological synapse. The microtubule motor protein cytoplasmic dynein clusters into a ring at the synapse, colocalizing with the ADAP ring. ADAP coprecipitates with dynein from activated Jurkat cells, and loss of ADAP prevents MTOC translocation and the specific recruitment of dynein to the synapse. These results suggest a mechanism that links signaling through the T cell receptor to translocation of the MTOC, in which the minus end-directed motor cytoplasmic dynein, localized at the synapse through an interaction with ADAP, reels in the MTOC, allowing for directed secretion along the polarized microtubule cytoskeleton.     

Synaptophysin regulates activity-dependent synapse formation in cultured hippocampal neurons.

Synaptophysin is an abundant synaptic vesicle protein without a definite synaptic function. Here, we examined a role for synaptophysin in synapse formation in mixed genotype micro-island cultures of wild-type and synaptophysin-mutant hippocampal neurons. We show that synaptophysin-mutant synapses are poor donors of presynaptic terminals in the presence of competing wild-type inputs. In homogenotypic cultures, however, mutant neurons display no apparent deficits in synapse formation compared with wild-type neurons. The reduced extent of synaptophysin-mutant synapse formation relative to wild-type synapses in mixed genotype cultures is attenuated by blockers of synaptic transmission. Our findings indicate that synaptophysin plays a previously unsuspected role in regulating activity-dependent synapse formation.     

The HTLV-1 Virological Synapse

Human T-lymphotropic virus-1 (HTLV-1) spreads efficiently between T-cells via a tight and highly organized cell-cell contact known as the virological synapse. It is now thought that many retroviruses and other viruses spread via a virological synapse, which may be defined as a virus-induced, specialized area of cell-to-cell contact that promotes the directed transmission of the virus between cells. We summarize here the mechanisms leading to the formation of the HTLV-1 virological synapse and the role played by HTLV-1 Tax protein. We propose a model of HTLV-1 transmission between T-cells based on the three-dimensional ultrastructure of the virological synapse. Finally, in the light of recent advances, we discuss the possible routes of HTLV-1 spread across the virological synapse.     

Different modes of hippocampal plasticity in response to estrogen in young and aged female rats

Estrogen regulates hippocampal dendritic spine density and synapse number in an N-methyl-D-aspartate (NMDA) receptor-dependent manner, and these effects may be of particular importance in the context of age-related changes in endocrine status. We investigated estrogen's effects on axospinous synapse density and the synaptic distribution of the NMDA receptor subunit, NR1, within the context of aging. Although estrogen induced an increase in axospinous synapse density in young animals, it did not alter the synaptic representation of NR1, in that the amount of NR1 per synapse was equivalent across groups. Estrogen replacement in aged female rats failed to increase axospinous synapse density; however, estrogen up-regulated synaptic NR1 compared with aged animals with no estrogen. Therefore, the young and aged hippocampi react differently to estrogen replacement, with the aged animals unable to mount a plasticity response generating additional synapses, yet responsive to estrogen with respect to additional NMDA receptor content per synapse. These findings have important implications for estrogen replacement therapy in the context of aging.     

Synapse turnover: the formation and termination of transient synapses.

Neurons dissociated from chick embryo retina form synapses with cultured rat striated muscle cells in 35-90 min when neurite extension is uncoupled from later steps in synapse formation. The results suggest that a reaction is required for synapse formation after neurons adhere to muscle cells. All synapses between retina neurons and muscle cells are terminated in 3-10 days depending on the developmental age of the neurons. The half-lives of synapses between muscle cells and retina neurons from 8-, 12-, or 13-day embryos are 36, 26, and 5 hr and mean synapse life-times are 53, 37, and 7.1 hr, respectively. The results show that synapses turn over and that the rate of turnover increases during development. The results suggest that both synapse formation and termination rates are regulated and that the specificity of synaptic connections can be increased by selective termination of synapses.     

Trans-synaptic EphB2–ephrin–B3 interaction regulates excitatory synapse density by inhibition of postsynaptic MAPK signaling

Nervous system function requires tight control over the number of synapses individual neurons receive, but the underlying cellular and molecular mechanisms that regulate synapse number remain obscure. Here we present evidence that a trans-synaptic interaction between EphB2 in the presynaptic compartment and ephrin-B3 in the postsynaptic compartment regulates synapse density and the formation of dendritic spines. Observations in cultured cortical neurons demonstrate that synapse density scales with ephrin-B3 expression level and is controlled by ephrin-B3–dependent competitive cell–cell interactions. RNA interference and biochemical experiments support the model that ephrin-B3 regulates synapse density by directly binding to Erk1/2 to inhibit postsynaptic Ras/mitogen-activated protein kinase signaling. Together these findings define a mechanism that contributes to synapse maturation and controls the number of excitatory synaptic inputs received by individual neurons.     

Transfer characteristics of a thermosensory synapse in Caenorhabditis elegans

Caenorhabditis elegans is a compact, attractive system for neural circuit analysis. An understanding of the functional dynamics of neural computation requires physiological analyses. We undertook the characterization of transfer at a central synapse in C. elegans by combining optical stimulation of targeted neurons with electrophysiological recordings. We show that the synapse between AFD and AIY, the first stage in the thermotactic circuit, exhibits excitatory, tonic, and graded release. We measured the linear range of the input-output curve and estimate the static synaptic gain as 0.056 (<0.1). Release showed no obvious facilitation or depression. Transmission at this synapse is peptidergic. The AFD/AIY synapse thus seems to have evolved for reliable transmission of a scaled-down temperature signal from AFD, enabling AIY to monitor and integrate temperature with other sensory input. Combining optogenetics with electrophysiology is a powerful way to analyze C. elegans' neural function.