血管内皮细胞线粒体氧化应激与动脉粥样硬化

血管内皮细胞损伤是动脉粥样硬化病理过程的起始环节。线粒体氧化应激与血管内皮细胞功能密切相关,线粒体氧化应激通过诱导线粒体自噬、一氧化氮生成减少、炎症反应、细胞代谢失衡和凋亡,导致血管内皮细胞的功能障碍。同时,血管内皮细胞也通过调控线粒体氧化应激维持自身稳态。本文旨在综述动脉粥样硬化病理过程中线粒体氧化应激诱发血管内皮细胞损伤的主要分子信号通路,为后续研究两者间的分子机制提供参考。     

炎症相关细胞在动脉粥样硬化发生发展过程中的作用

炎症反应为动脉粥样硬化(AS)发生发展过程中的核心因素。与炎症相关的细胞,如血管内皮细胞、单核/巨噬细胞、T淋巴细胞和血管平滑肌细胞,及其分泌的细胞因子与AS的发生、发展密切相关。因此,认识AS病理过程中炎症细胞间的相互作用机制并加以干预,是目前防治AS研究的一个重要方向。     

Rho激酶在动脉粥样硬化和血管疾病中的重要作用

动脉粥样硬化是一个复杂的炎症过程,其特征是进展性的炎症和血脂的聚集交互作用.它的发展部分起源于内皮细胞的功能失调导致内皮细胞的激活和前炎症细胞的聚集.局部的炎症促进白细胞和血小板聚集到受损的内皮细胞,导致血管对血浆中血脂成分的渗透性增加,结果单核细胞负载着脂质成分聚集在动脉内膜并获得巨噬细胞的形态学上的特征转化成泡沫细胞.随着另外的炎症细胞及细胞内血脂的聚集,这些早期的斑块,即脂质条纹进展到成熟的动脉硬化斑块.斑块通过分泌细胞因子和生长因子而促进它们自己的生长导致细胞内基质成分的沉淀,进而斑块扩大形成血管的狭窄.     

氧化应激与动脉粥样硬化

许多疾病状态如高血压、糖尿病、高血糖症等使体内产生过多的活性氧,导致产生氧化应激状态.ROS除线粒体呼吸链产生外,在血管细胞主要有NADH/NADPH氧化酶、黄嘌呤氧化酶、内皮细胞一氧化氮合酶等酶性来源.研究发现,ROS主要通过改变基因表达、刺激某些细胞因子分泌和加速一些蛋白质的氧化磷酸化等方式,改变内皮细胞功能,使单核细胞增殖、粘附并移行至内皮下,导致血管平滑肌细胞增殖、移行和发生炎性免疫反应,导致或促进动脉粥样硬化病变.     

单核细胞/高密度脂蛋白比值与阻塞性睡眠呼吸暂停综合征相关性分析

<正>阻塞性睡眠呼吸暂停综合征(OSAS)是一种以反复上呼吸道阻塞为特征并伴有鼾声和白天嗜睡的临床疾病。OSAS与心血管疾病和脑血管疾病的风险增加有关。OSAS也与血脂异常相关,OSAS患者可引起动脉粥样硬化和冠心病。严重OSAS患者甘油三酯、总胆固醇和低密度脂蛋白水平升高,而高度脂蛋白水平降低[1]。而冠心病发生与动脉粥样硬化的炎症反应相关。冠心病患者白细胞、中性粒细胞、淋巴细胞、单核细胞和嗜酸性粒细胞增多,而且与预后不良有关[2]。单核细胞在动脉粥样硬化血管内皮损伤中发挥关键作用。以往研究报道,低高密度脂蛋白水平与高单核细胞计数相关,而且高单核细胞/高密度脂蛋白比值(MHR)水平也是心血管疾病危     

阻塞性睡眠呼吸暂停综合征与心血管疾病炎症反应的研究进展

阻塞性睡眠呼吸暂停综合征(OSAS)以间歇低氧为核心特点,可导致心血管系统发生氧化应激而引起全身炎症反应.OSAS发病率较高,已成为心血管疾病发病的常见独立危险因素,其中炎症反应可能在OSAS引起的心血管疾病中起到了关键作用,本文旨在针对近年来关于OSAS与心血管疾病炎症反应的研究进展作一概述.     

病毒性肝炎发病的免疫学机制与抗肝炎新药研究的思考

免疫反应在病毒导致的肝损伤和自身免疫性肝炎的发病机制中起着重要的作用。无效的免疫反应不仅不能清除病毒 ,相反导致肝细胞的持续损伤。肝损伤的免疫学机制涉及到多种细胞 ,包括淋巴细胞、单核巨噬细胞 (Kupffer细胞 )、肝内皮细胞、肝实质细胞和星状细胞。淋巴细胞的激活是免疫介导肝损伤的起始步骤。激活的淋巴细胞通过死亡配体和受体的结合诱导肝细胞的凋亡。淋巴细胞进一步激活巨噬细胞 ,导致多种炎症细胞因子的释放 ,继而导致细胞死亡级联反应 ,介导肝损伤。对肝细胞免疫损伤机制的探讨为研制防治肝病的药物提供了新的思路     

红景天苷及其苷元酪醇的心血管保护作用

本文综述了红景天苷及其苷元酪醇对心血管的主要保护作用:①抗氧化作用,促进一氧化氮合成和抑制炎症介质前列腺素合成。②激活PI3K/Akt信号转导通路,上调缺氧诱导因子-1和血管内皮生长因子表达及Bcl-2/Bax比值。③抑制线粒体通透性转换孔开放,维护线粒体跨膜电位,阻滞半胱天冬酶-3激活,保护心肌细胞和血管内皮细胞。红景天苷和酪醇对抗缺血、缺氧、缺血再灌注或氧化应激引起的心血管细胞损伤,抑制氧化修饰的低密度脂蛋白形成、血管平滑肌细胞增殖和血小板聚集,降低血液粘度等,阻碍动脉粥样硬化发生和发展,产生心血管保护作用。     

动脉粥样硬化相关miRNA研究进展

<正>动脉粥样硬化(AS)是一种严重危害人类健康的血管慢性疾病,是由炎症、免疫机制以及脂质浸润等多种因素参与的综合性病变[1]。它的主要表现是大量胆固醇酯在大中型动脉血管壁内堆积形成粥样硬化斑块,最终导致动脉血管壁增厚、血管腔变窄或破裂,拥有极高的发病率和死亡率。作为炎症性疾病,AS病变先是从氧化应激导致血管内皮功能发生障碍开始,随后低密度脂蛋白(LDL)透过内皮细胞     

氧化低密度脂蛋白致血管内皮损伤机制及中药复方防治的研究进展

低密度脂蛋白经氧化修饰后主要通过凝集素样氧化低密度脂蛋白受体-1导致管内皮细胞损伤,诱导黏附分子和炎症因子的合成与释放,加重血管炎症反应,诱导内皮细胞凋亡,进而导致动脉粥样硬化等心血管疾病.中药复方通过抑制低密度脂蛋白(LDL)氧化生成氧化低密度脂蛋白(OX-LDL),防治血管内皮损伤,进而防治动脉粥样硬化的发生与发展...     

Oxidative stress, antioxidants, and endothelial function

Endothelial dysfunction, characterized by a loss in nitric oxide bioactivity, is an early event in the development of atherosclerosis and determines future vascular complications. Emerging evidence suggests a causal role for oxidative stress in this process. Reactive oxygen species can directly inactivate nitric oxide, modulate protein function and act as cellular signaling molecules. These events contribute to the initiation and progression of endothelial dysfunction. Considerable data also indicates that antioxidant compounds limit oxidative damage and restore endothelial function. The purpose of this review is to discuss these data and suggest novel approaches for lowering the oxidative stress in the vasculature.     

Baroreflex deficiency aggravates atherosclerosis via α7 nicotinic acetylcholine receptor in mice

ObjectiveInflammation and oxidative stress play a key role in the initiation, propagation, and development of atherosclerosis. Arterial baroreflex (ABR) dysfunction induced by sinoaortic denervation (SAD) promoted the development of atherosclerosis in ApoE^−/− mice. The present work was designed to examine whether ABR deficiency affected inflammation and oxidative stress via α7 nicotinic acetylcholine receptor (α7nAChR) leading to the aggravation of atherosclerosis in mice.Methods and resultsApoE^−/− mice were fed with a high-cholesterol diet for 6 weeks and half of the mice received sinoaortic denervation that destroyed ABR. We studied the expression of vesicular acetylcholine transporter (VAChT), α7nAChR and levels of inflammatory response and oxidative stress. The results showed that baroreflex dysfunction could promote atherosclerosis, meanwhile, decrease the expression of VAChT and α7nAChR and significantly increase the levels of oxidative stress and inflammation in SAD mice. After treated with PNU-282987 (a selective α7nAChR agonist, 0.53 mg/kg/day) for 6 weeks in SAD and Sham mice, we found that PNU-282987 could attenuate atherosclerosis and significantly decreased oxidative stress and inflammation after SAD. In addition, α7nAChR^+/+ and α7nAChR^−/− mice fed with a high-cholesterol diet for 8 weeks were co-treated with ketanserin (0.6 mg/kg/day), a drug that can enhance baroreflex sensitivity (BRS). Ketanserin could alleviate atherosclerosis and markedly decrease oxidative stress and inflammation in α7nAChR^+/+ mice. But there were no effects in α7nAChR knockout mice.ConclusionsOur results demonstrate that ABR dysfunction aggravates atherosclerosis in mice via the vagus-ACh-α7nAChR-inflammation and oxidative stress pathway.     

The role of oxidative stress,antioxidants and vascular inflammation in cardiovascular disease (a review)

The concept of mild chronic vascular inflammation as part of the pathophysiology of cardiovascular disease, most importantly hypertension and atherosclerosis, has been well accepted. Indeed there are links between vascular inflammation, endothelial dysfunction and oxidative stress. However, there are still gaps in our understanding regarding this matter that might be the cause behind disappointing results of antioxidant therapy for cardiovascular risk factors in large-scale long-term randomised controlled trials. Apart from the limitations of our knowledge, limitations in methodology and assessment of the body's endogenous and exogenous oxidant-antioxidant status are a serious handicap. The pleiotropic effects of antioxidant and anti-inflammation that are shown by some well-established antihypertensive agents and statins partly support the idea of using antioxidants in vascular diseases as still relevant. This review aims to provide an overview of the links between oxidative stress, vascular inflammation, endothelial dysfunction and cardiovascular risk factors, importantly focusing on blood pressure regulation and atherosclerosis. In view of the potential benefits of antioxidants, this review will also examine the proposed role of vitamin C, vitamin E and polyphenols in cardiovascular diseases as well as the success or failure of antioxidant therapy for cardiovascular diseases in clinical trials.     

Sirt1在心血管衰老中的作用机制研究进展

Sirt1是依赖于烟酰胺腺嘌呤二核苷酸（NAD⁺）的一类高度保守的去乙酰化酶,可将多种组蛋白和非组蛋白去乙酰化参与胰岛素分泌、血管生成、神经保护及细胞衰老等生理过程。Sirt1与心血管疾病、神经退行性疾病等衰老相关疾病的发病机理密切关系。在心血管系统中,大量研究证实,Sirt1可延缓内皮细胞衰老,改善内皮细胞功能,维持血管内稳定,从而对动脉粥样硬化、缺血再灌注损伤、心血管衰老具有重要调节作用。目前,Sirt1作为一个长寿因子受到普遍关注。本文主要从氧化应激、炎症、自噬三个方面阐述Sirt1对心血管衰老的作用机制,为寻求和研发延缓心血管衰老药物提供实验依据。     

细胞自噬在动脉粥样硬化发生发展中的作用

细胞自噬是生物体内清除功能异常的细胞器、错误折叠的蛋白质、被氧化的脂类等有害大分子物质的重要途径。在动脉粥样硬化中的作用具有双重性,不仅作为抵御环境变化对细胞造成损害的防御机制,又可以诱导细胞Ⅱ型程序性死亡,如何调控自噬在动脉粥样硬化的防治中至关重要。巨噬细胞、血管内皮细胞和血管平滑肌细胞的自噬参与动脉粥样硬化发生发展过程,在斑块的形成和破裂中发挥潜在作用。深入了解细胞自噬与动脉粥样硬化的关系,将有可能为动脉粥样硬化的药物防治提供新的治疗靶点。     

PCB-induced endothelial cell dysfunction: Role of poly(ADP-ribose) polymerase

Polychlorinated biphenyls (PCBs) are persistent environmental pollutants implicated in the development of pro-inflammatory events critical in the pathology of atherosclerosis and cardiovascular disease. PCB exposure of endothelial cells results in increased cellular oxidative stress, activation of stress and inflammatory pathways leading to increased expression of cytokines and adhesion molecules and ultimately cell death, all of which can lead to development of atherosclerosis. To date no studies have been performed to examine the direct effects of PCB exposure on the vasculature relaxant response which if impaired may predispose individuals to hypertension, an additional risk factor for atherosclerosis. Overactivation of the DNA repair enzyme poly(ADP-ribose) polymerase (PARP) following oxidative/nitrosative stress in endothelial cells and subsequent depletion of NADPH has been identified as a central mediator of cellular dysfunction. The aim therefore was to investigate whether 2,2′,4,6,6′-pentachlorobiphenyl (PCB 104) directly causes endothelial cell dysfunction via increased oxidative stress and subsequent overactivation of PARP. Exposure of ex vivo rat aortic rings to PCB 104 impaired the acetylcholine-mediated relaxant response, an effect that was dependent on both concentration and exposure time. In vitro exposure of mouse endothelial cells to PCB 104 resulted in increased cellular oxidative stress through activation of the cytochrome p450 enzyme CYP1A1 with subsequent overactivation of PARP and NADPH depletion. Pharmacological inhibition of CYP1A1 or PARP protected against the PCB 104-mediated endothelial cell dysfunction. In conclusion, the environmental contaminants, PCBs, can activate PARP directly impairing endothelial cell function that may predispose exposed individuals to development of hypertension and cardiovascular disease.     

Endothelial dysfunction and coronary atherosclerosis

Increasing evidence has revealed that endothelial cells play an important role in the pathogenesis of development and progression of atherosclerosis. Endothelial dysfunction induces disruption of the balance between vasoconstrictive factors and vasodilatory factors secreted from endothelial cells. Among these factors, NO and angiotensin II are especially important factors, and have been shown to exert various direct effects on the endothelial functions that are closely related to the pathogenesis of atherosclerosis. Endothelial dysfunction induces decreased NO bioactivity and increased angiotensin II expression, which increase oxidative stress and expression of adhesion molecules, cytokines, and chemokines. These conditions mediate inflammation, proliferation, and thrombogenesis in vessel wall and promote atherosclerotic lesions. On the other hand, therapies that improve endothelial dysfunction, such as administration of HMG-CoA reductase inhibitors or angiotensin converting inhibitors, have been demonstrated to reduce cardiovascular events and strokes. In this article, we focus on NO and angiotensin II and describe their roles in the pathogenesis of atherosclerosis.     

Antioxidant Activity of Plicatin B on Cultured Human Microvascular Endothelial Cells Exposed to H2O2

Oxidative stress plays a crucial role in the pathogenesis of atherosclerosis by promoting endothelial dysfunction and impairing vascular relaxation. Flavonoids are largely investigated for their biological properties and particularly for their scavenging and antioxidant properties. In the current study, we evaluated the clastogenicity of the chalcone plicatin B in peripheral human lymphocytes (whole blood and pure lymphocytes) as well as its antioxidant activity and its ability to contrast dysfunction on human microvascular endothelial cells (HMEC-1) exposed to hydrogen peroxide. We measured in the cell culture medium the levels of 8-isoprostane, NO_x, ET-1, and ICAM-1, as well as the expression of e-NOS, prepro-ET-1, and ICAM-1. In conclusion, our results demonstrate that the chalcone plicatin B (1–10 μM) may represent a good candidate for the prevention of atherosclerosis, as it consistently reduces the oxidative/inflammatory process and is not genotoxic to human lymphocytes.     

Antioxidant activity of plicatin B on cultured human microvascular endothelial cells exposed to H2O2

Oxidative stress plays a crucial role in the pathogenesis of atherosclerosis by promoting endothelial dysfunction and impairing vascular relaxation. Flavonoids are largely investigated for their biological properties and particularly for their scavenging and antioxidant properties. In the current study, we evaluated the clastogenicity of the chalcone plicatin B in peripheral human lymphocytes (whole blood and pure lymphocytes) as well as its antioxidant activity and its ability to contrast dysfunction on human microvascular endothelial cells (HMEC-1) exposed to hydrogen peroxide. We measured in the cell culture medium the levels of 8-isoprostane, NOx, ET-1, and ICAM-1, as well as the expression of e-NOS, prepro-ET-1, and ICAM-1. In conclusion, our results demonstrate that the chalcone plicatin B (1-10 microM) may represent a good candidate for the prevention of atherosclerosis, as it consistently reduces the oxidative/inflammatory process and is not genotoxic to human lymphocytes.