活性氧在中性粒细胞胞外诱捕网形成中的作用

中性粒细胞胞外诱捕网(NETs)是胞外的一种DNA网状结构,其可网罗、杀伤病原体从而参与机体固有免疫应答.然而在某些情况下NETs会引发一系列自身免疫性疾病.研究表明,在NETs形成过程中活性氧(ROS)起到至关重要的作用.阐述活性氧与NETs形成的相互作用,进一步讨论了尚未完全明确的活性氧与NETs的关系,包括还原型烟酰胺腺嘌呤二核苷酸磷酸(NADPH)氧化酶产生的ROS的作用,依赖NADPH氧化酶产生NETs的分子机制,以及非NADPH氧化酶产生的ROS的作用,从多方面分析ROS与NETs形成的关系.     

NADPH氧化酶与脑缺血/再灌注损伤

氧化应激是发生脑缺血/再灌注(ischemia/reperfusion,I/R)损伤的重要机制.近来研究发现,还原型烟酰胺腺嘌呤二核苷酸磷酸(nicotinamide adenine dinucleotide phosphate,NADPH)氧化酶产生的活性氧对脑I/R后的氧化应激起到重要的作用.一些方法(如常压高氧、缺血后处理)和一些药物(如罗布麻宁、替米沙坦、桦木酸、加兰他敏、雷公藤红素等)可以NADPH氧化酶为靶点治疗脑I/R损伤.     

移植血管外膜早期NADPH氧化酶激活和新生血管形成

<正>目的:动脉外膜所产生的活性氧和新生血管形成,可能导致和促进病理性血管重构的形成。本课题研究NADPH氧化酶在同种异体主动脉移植模型的外膜血管动态表达和新生血管形成。方法:将F344大鼠胸主动脉移植到Lewis腹主动脉造模。于移植后0.5、3、7和14 d收集移植血管,进行形态学分析、免疫组化和定量PCR检测。结果:血管外膜移植后3 d、内膜7 d     

活性氧在高血压过程中的作用

在实验性高血压以及人体高血压中均显示活性氧生成明显增多,血管中通过NADP(H)氧化酶以及NOS解偶联而产生的活性氧(ROS)参与了高血压过程中血管功能的损害及血管的炎性反应。运用抗氧化治疗有利于减小对血管的损伤,降低高血压生成的终末器官损害。     

NAD（P）H氧化酶及其在高血压血管损害中的作用

血管活性氧簇 (ROS)尤其是超氧阴离子 (·O2 )的增加 ,在高血压引起的血管功能和结构改变中起重要作用。NAD(P)H氧化酶是血管产生·O2 的主要酶 ,并参与了这一损伤机制。     

NADPH氧化酶NOX家族的组织分布及生理功能

NADPH 氧化酶特异存在于吞噬细胞质膜，能生成用于清除病原微生物的活性氧(reactive oxygen species, ROS)。最近发现吞噬细胞NADPH氧化酶的6个同源物即NOX1, NOX3, NOX4, NOX5, DUOX1, DUOX2。NADPH 氧化酶催化亚基gp91phox/NOX2及其同源物统称为NOX家族蛋白。这些酶能通过质膜传递电子产生活性氧(ROS)。NOX家族不同成员的激活机制及分布是不同的。NOX激活多条信号转导通路，调节细胞的生长、增殖、分化等，NOX缺陷会导致免疫抑制，如DUOX2突变可以导致甲状腺功能减低症。     

Nox2来源的活性氧促进小鼠诱导性多能干细胞向动脉内皮细胞分化

<正>目的:活性氧(ROS)调节诱导性多能干细胞(iP SCs)向内皮细胞分化的分子机制还不清楚。本研究旨在探讨NADPH氧化酶2(Nox2)来源的ROS在iP SCs向内皮细胞分化中的作用和分子机制。方法和结果:我们利用野生型和Nox2基因缺失型小鼠胚胎成纤维细胞,诱导生成小鼠iP SCs,发现Nox2基因缺失的小鼠iP SCs分化的血管内皮细胞(Nox2-/-miP SC-ECs)中,     

NADPH氧化酶NOX家族与疾病的关系

还原型烟酰胺腺嘌呤二核苷酸磷酸(nicotinamide adenine dinucleotide phosphate, NADPH)氧化酶的非吞噬细胞氧化酶(non-phagocytic cell oxidase, NOX)家族是许多非吞噬细胞中活性氧(reactive oxygen species, ROS)的主要来源.正常状态下,通过该途径产生的ROS作为信号分子参与了细胞分化、增殖、凋亡等的调节,但在环境胁迫下,NOX蛋白家族在感受细胞外信息刺激时,能够迅速活化产生过量的ROS,引起的氧化压力会诱导机体多种疾病的发生、发展.本文主要从NADPH氧化酶NOX家族蛋白的结构、活化、功能及与疾病发生、发展的关系等方面进行简述.     

脂筏在高血压发病机制中的作用

原发性高血压的发病机制尚未完全明确,随着脂筏结构与功能的不断阐明,它与高血压之间的关系越来越密切。脂筏与细胞的许多重要功能有关,高血压的多种信号转导事件的发生是通过定位于脂筏及caveolae的细胞膜受体,所以脂筏在高血压的发生发展过程中起了重要的调控作用。与高血压发病机制相关的因素,如内皮型一氧化氮合成酶、细胞外钙受体、NADPH氧化酶、Rho激酶、胰岛素受体、Ca2+以及转化生长因子和丝裂原蛋白激酶信号转导通路等,这些蛋白和信号分子都定位于脂筏或者受脂筏调控,从而为脂筏与高血压发病机制之间的关系提供了更加充分的证据。本文将对各相关蛋白和信号转导与高血压的形成原因作一综述。     

NADPH氧化酶在TNF-α诱导HUVEC HO-1表达中的作用

目的探讨NADPH氧化酶来源的活性氧(ROS)在TNF-α诱导人脐静脉内皮细胞(HUVEC)血红素氧化酶1(HO-1)表达中的作用。方法用小分子RNA干扰(siRNA)技术消除HUVEC的NADPH氧化酶p47phox亚基,用分子探针2,7-DCF测定细胞内ROS的产生量以及用RT-PCR测定HO-1 mRNA的表达。结果TNF-α(200 U/mL)作用24 h后,HUVEC中ROS的产生量增加了138%,细胞内HO-1 mRNA表达较对照组增加146.5%;转染p47phoxsiRNA后,细胞内NADPH氧化酶p47phox亚基的mRNA表达消失,ROS的产生量降低至对照组水平,而HO-1 mRNA的表达水平降低约54%。结论TNF-α刺激后,HUVEC内产生的ROS主要来源于NADPH氧化酶的活化,但ROS仅部分介导了TNF-α对HO-1基因表达的诱导作用。     

Oxidative stress and vascular remodelling

Oxidative stress plays an important role in the pathophysiology of vascular diseases. Reactive oxygen species, especially superoxide anion and hydrogen peroxide, are important signalling molecules in cardiovascular cells. Enhanced superoxide production increases nitric oxide inactivation and leads to an accumulation of peroxynitrites and hydrogen peroxide. Reactive oxygen species participate in growth, apoptosis and migration of vascular smooth muscle cells, in the modulation of endothelial function, including endothelium-dependent relaxation and expression of proinflammatory phenotype, and in the modification of the extracellular matrix. All these events play important roles in vascular diseases such as hypertension, suggesting that the sources of reactive oxygen species and the signalling pathways that they modify may represent important therapeutic targets. Potential sources of vascular superoxide production include NADPH-dependent oxidases, xanthine oxidases, lipoxygenases, mitochondrial oxidases and nitric oxide synthases. Studies performed during the last decade have shown that NADPH oxidase is the most important source of superoxide anion in phagocytic and vascular cells. Evidence from experimental animal and human studies suggests a significant role of NADPH oxidase activation in the vascular remodelling and endothelial dysfunction found in cardiovascular diseases.     

The role of NADPH oxidase in chronic intermittent hypoxia-induced pulmonary hypertension in mice

Obstructive sleep apnea, characterized by intermittent periods of hypoxemia, is an independent risk factor for the development of pulmonary hypertension. However, the exact mechanisms of this disorder remain to be defined. Enhanced NADPH oxidase expression and superoxide (O2(-).) generation in the pulmonary vasculature play a critical role in hypoxia-induced pulmonary hypertension. Therefore, the current study explores the hypothesis that chronic intermittent hypoxia (CIH) causes pulmonary hypertension, in part, by increasing NADPH oxidase-derived reactive oxygen species (ROS) that contribute to pulmonary vascular remodeling and hypertension. To test this hypothesis, male C57Bl/6 mice and gp91phox knockout mice were exposed to CIH for 8 hours per day, 5 days per week for 8 weeks. CIH mice were placed in a chamber where the oxygen concentration was cycled between 21% and 10% O2 45 times per hour. Exposure to CIH for 8 weeks increased right ventricular systolic pressure (RVSP), right ventricle (RV):left ventricle (LV) + septum (S) weight ratio, an index of RV hypertrophy, and thickness of the right ventricular anterior wall as measured by echocardiography. CIH exposure also caused pulmonary vascular remodeling as demonstrated by increased muscularization of the distal pulmonary vasculature. CIH-induced pulmonary hypertension was associated with increased lung levels of the NADPH oxidase subunits, Nox4 and p22phox, as well as increased activity of platelet-derived growth factor receptor beta and its associated downstream effector, Akt kinase. These CIH-induced derangements were attenuated in similarly treated gp91phox knockout mice. These findings demonstrate that NADPH oxidase-derived ROS contribute to the development of pulmonary vascular remodeling and hypertension caused by CIH.     

NADPH oxidases in cardiovascular health and disease

Increased oxidative stress plays an important role in the pathophysiology of cardiovascular diseases such as hypertension, atherosclerosis, diabetes, cardiac hypertrophy, heart failure, and ischemia-reperfusion. Although several sources of reactive oxygen species (ROS) may be involved, a family of NADPH oxidases appears to be especially important for redox signaling and may be amenable to specific therapeutic targeting. These include the prototypic Nox2 isoform-based NADPH oxidase, which was first characterized in neutrophils, as well as other NADPH oxidases such as Nox1 and Nox4. These Nox isoforms are expressed in a cell- and tissue-specific fashion, are subject to independent activation and regulation, and may subserve distinct functions. This article reviews the potential roles of NADPH oxidases in both cardiovascular physiological processes (such as the regulation of vascular tone and oxygen sensing) and pathophysiological processes such as endothelial dysfunction, inflammation, hypertrophy, apoptosis, migration, angiogenesis, and vascular and cardiac remodeling. The complexity of regulation of NADPH oxidases in these conditions may provide the possibility of targeted therapeutic manipulation in a cell-, tissue- and/or pathway-specific manner at appropriate points in the disease process.     

NADPH oxidase(s): new source(s) of reactive oxygen species in the vascular system?

Reactive oxygen species play an important role in a variety of (patho)physiological vascular processes. Recent publications have produced evidence of a role for putative non-phagocyte NADP oxidase(s) in the vascular production of reactive oxygen species. In the present review, we discuss the detection of the different components of NADP oxidase(s) in the vascular system, together with the putative role of reactive oxygen species produced by vascular NADPH oxidase(s), in both in vitro and in vivo studies.     

NADPH oxidases in the kidney

NADPH oxidases have a distinct cellular localization in the kidney. Reactive oxygen species (ROS) are produced in the kidney by fibroblasts, endothelial cells (EC), vascular smooth muscle cells (VSMC), mesangial cells (MCs), tubular cells, and podocyte cells. All components of the phagocytic NADPH oxidase, as well as the Nox-1 and -4, are expressed in the kidney, with a prominent expression in renal vessels, glomeruli, and podocytes, and cells of the thick ascending limb of the loop of Henle (TAL), macula densa, distal tubules, collecting ducts, and cortical interstitial fibroblasts. NADPH oxidase activity is upregulated by prolonged infusion of angiotensin II (Ang II) or a high salt diet. Since these are major factors underlying the development of hypertension, renal NADPH oxidase may have an important pathophysiological role. Indeed, recent studies with small interference RNAs (siRNAs) targeted to p22( phox ) implicate p22( phox ) in Ang II-induced activation of renal NADPH oxidase and the development of oxidative stress and hypertension, while studies with apocynin implicate activation of p47( phox ) in the development of nephropathy in a rat model of type 1 diabetes mellitus (DM). Experimental studies of the distribution, signaling, and function of NADPH oxidases in the kidney are described.     

Suppression of oxidative stress in the endothelium and vascular wall.

There is growing evidence that oxidative stress, meaning an excessive production of reactive oxygen and nitrogen species, underlies many forms of cardiovascular disease. The major source of oxidative stress in the artery wall is an NADPH oxidase. This enzyme complex in vascular cells, including endothelium, differs from that in phagocytic leucocytes in both biochemical structure and functions. The crucial flavin-containing catalytic subunits Nox1 and Nox4 are not present in leucocytes, but are highly expressed in vascular cells and upregulated in vascular remodeling, such as that found in hypertension and atherosclerosis. This offers the opportunity to develop "vascular specific" NADPH oxidase inhibitors that do not compromise the essential physiological signaling and phagocytic function carried out by reactive oxygen and nitrogen molecules. Although many conventional antioxidants fail to significantly affect outcomes in cardiovascular disease, targeted inhibitors of NADPH oxidase that block the source of oxidative stress in the vasculature are more likely to prevent the deterioration of vascular function that leads to stroke and heart attack.     

NADPH oxidase-mediated oxidative stress: genetic studies of the p22(phox) gene in hypertension

Increased vascular production of reactive oxygen species, especially superoxide anion, significantly contributes to the oxidative stress associated with hypertension. An enhanced superoxide production causes an increased inactivation of nitric oxide that diminishes nitric oxide bioavailability, thus contributing to endothelial dysfunction and hypertrophy of vascular cells. It has been shown that NADPH oxidases play a major role as the most important sources of superoxide anion in phagocytic and vascular cells. Several experimental observations have described an enhanced superoxide generation as a result of NADPH oxidase activation in hypertension. Although these enzymes respond to stimuli such as vasoactive factors, growth factors, and cytokines, recent data suggest a significant role of the genetic background in the modulation of the expression of its different components. Several polymorphisms have been identified in the promoter and in the coding region of CYBA, the gene that encodes the essential subunit of the NADPH oxidase p22phox, some of which seem to influence significantly the activity of these enzymes in the context of cardiovascular diseases. Among CYBA polymorphisms, genetic investigations have provided a novel marker, the -930(A/G) polymorphism, which determines the genetic susceptibility of hypertensive patients to oxidative stress.     

血管NAD(P)H氧化酶在血管重塑中的作用

NAD(P)H oxidase was initially found in phagocytes and it participates in the generation of reactive oxygen species(ROS). Recent researches have showed that NAD(P)H oxidase also expresses in other tissues including blood vessels and it plays a critical role in vascular remodeling through ROS which are important signaling molecules in vascular cells. This article reviews the biochemical characterization, activation paradigms, structure, and function of this enzyme.     

Regulation of NADPH oxidase in vascular endothelium: the role of phospholipases, protein kinases, and cytoskeletal proteins

The generation of reactive oxygen species (ROS) in the vasculature plays a major role in the genesis of endothelial cell (EC) activation and barrier function. Of the several potential sources of ROS in the vasculature, the endothelial NADPH oxidase family of proteins is a major contributor of ROS associated with lung inflammation, ischemia/reperfusion injury, sepsis, hyperoxia, and ventilator-associated lung injury. The NADPH oxidase in lung ECs has most of the components found in phagocytic oxidase, and recent studies show the expression of several homologues of Nox proteins in vascular cells. Activation of NADPH oxidase of nonphagocytic vascular cells is complex and involves assembly of the cytosolic (p47(phox), p67(phox), and Rac1) and membrane-associated components (Noxes and p22(phox)). Signaling pathways leading to NADPH oxidase activation are not completely defined; however, they do appear to involve the cytoskeleton and posttranslation modification of the components regulated by protein kinases, protein phosphatases, and phospholipases. Furthermore, several key components regulating NADPH oxidase recruitment, assembly, and activation are enriched in lipid microdomains to form a functional signaling platform. Future studies on temporal and spatial localization of Nox isoforms will provide new insights into the role of NADPH oxidase-derived ROS in the pathobiology of lung diseases.     

Targeting reactive oxygen species in hypertension

Oxidative stress plays an important role in the pathogenesis of hypertension. A number of sources of reactive oxygen species have been identified including NADPH oxidase, endothelial NO synthase, and xanthine oxidase. Inhibitors of these systems reduce blood pressure in experimental models. Targeted overexpression of antioxidant systems and interference with expression of oxidant systems has also been successfully used in animal models of hypertension. It is expected that these strategies will eventually be translated to human disease, but currently, the specificity and toxicity of such measures are not yet fulfilling quality criteria for treatment of humans. In the meantime, presumably nontoxic measures, such as administration of antioxidant vitamins, are the only available treatments for oxidative stress in humans. In this review, we discuss strategies to target oxidative stress both in experimental models and in humans. We also discuss how patients could be selected who particularly benefit from antioxidant treatment. In clinical practice, diagnostic procedures beyond measurement of blood pressure will be necessary to predict the response to antioxidants; these procedures will include measurement of antioxidant status and detailed assessment of vascular structure and function.