Endothelial Dysfunction and Vascular Inflammation
内皮功能障碍和血管炎症
基本信息
- 批准号:7733531
- 负责人:
- 金额:$ 7.73万
- 依托单位:
- 依托单位国家:美国
- 项目类别:
- 财政年份:
- 资助国家:美国
- 起止时间:至
- 项目状态:未结题
- 来源:
- 关键词:2,4-thiazolidinedioneAcetatesAcuteAffectAnti-Inflammatory AgentsAnti-inflammatoryAntibioticsAppearanceArginineAscaridilAtherosclerosisBinding SitesBloodBlood CirculationBlood PlateletsBlood VesselsCDKN1A geneCalciumCardiovascular systemCause of DeathCell LineCellsCessation of lifeChronicClinical TrialsConditionConstriction procedureDevelopmentDown-RegulationDrug usageEndothelial CellsEndotheliumFailureFeedbackFunctional disorderGenomicsHumanHybridsHypotensionIllness DaysImmune systemInfectionInflammationInflammatoryInjuryIntensive Care UnitsInvestigationIonophoresKnowledgeLinkMAP Kinase GeneMAPK14 geneMediator of activation proteinMessenger RNAMetabolismMutationMyristatesNADPNitric OxideNon-Insulin-Dependent Diabetes MellitusNuclear ReceptorsOutputOxidantsPPAR gammaPathologicPatientsPeroxisome Proliferator-Activated ReceptorsPhenotypePhorbolPhorbolsPlayProductionReactive Oxygen SpeciesRefractoryRelaxationRestRiskRoleSepsisSeptic ShockSeriesShockSickle Cell AnemiaSignal PathwaySignal Transduction PathwaySiteStressSuperoxide DismutaseSuperoxidesSupportive careSurvivorsTestingThiazolidinedionesTransfectionU937 CellsUmbilical veinUnited StatesVasoconstrictor AgentsWorkbasehuman NOS3 proteinhuman PLK1 proteininhibitor/antagonistmecarzolemyristateoncoprotein p21preventpromoterresponsesensorvascular inflammation
项目摘要
Transfection of monoblastoid U937 cells with human eNOS (endothelial nitric oxide synthase) resulted in a cell line that produces nitric oxide (NO) in response to a calcium ionophore, but little or no NO in the resting state (Blood, 1997). However, after differentiation with phorbol-12-acetate-13-myristate, eNOS expressing cells produced increased amounts of both TNFalpha and reactive oxygen species by mechanisms that were independent of NO. Neither N-omega-methyl-L-arginine, a NOS inhibitor, nor mutation of the L-arginine binding site of eNOS (rendering it incapable of producing nitric oxide) blocked the ability of eNOS to upregulate TNFalpha (J Biol Chem, 2000). Conversely, co-transfection with superoxide dismutase or deletion of the NADPH binding site of eNOS completely prevented eNOS from upregulating TNFalpha production. Ultimately, superoxide produced by eNOS was shown to upregulate TNFalpha via Erk1/2 activation (J Biol Chem, 2001). This series of investigations demonstrated that while high output NO from inducible NOS can enhance inflammation (J Immunol, 1994; J Biol Chem, 1997), dysregulation of eNOS can also contribute to an inflammatory phenotype through reactive oxygen species-based signal transduction pathways.
Sp1 was shown to act as a sensor of high-output NO, down regulating eNOS in endothelial cells via a proximal Sp promoter-binding site (J Biol Chem, 2003). This work defined a key negative feedback mechanism that suppresses eNOS and reinforces vascular dysfunction in septic shock.
Sickle cell disease was characterized by oxidant and inflammatory stress in the vasculature, even in the absence of an acute crisis (Blood, 2004). Circulatory stress in sickle cell disease was associated with abnormalities of arginine metabolism in platelets (Circulation, 2007), further characterizing this condition as an NO-deficient state.
Anti-proliferative effects of NO that prevent the development of a chronic vascular injury phenotype was linked to p38 MAPK activation and p21 mRNA stabilization with subsequent down regulation of polo-like kinase 1 through a CDE/CHR proximal promoter site (BMC Genomics, 2005; J Biol Chem, 2006). This and later investigations (see below) indicate that p38 MAPK may play a protective role in the vasculature under some conditions.
Both NO and peroxisome proliferator-activated receptors (PPARs) protect the endothelium and regulate its function. Therefore, we tested for crosstalk between these signaling pathways using human umbilical vein and hybrid EA.hy926 endothelial cells (FASEB J, 2007). PPARgamma was activated by NO through a p38 MAPK dependent signal transduction pathway. This crosstalk mechanism may contribute to the anti-inflammatory and cytoprotective effects of NO in the vasculature. Recent work has shown that p38 MAPK is also necessary for the optimal activation of PPAR gamma by thiazolidinediones (TZDs), drugs used in the treatment of type 2 diabetes mellitus. TZDs, like homeostatic NO production, reduce markers of cardiovascular inflammation. Collectively, these findings suggest that PPAR gamma as well as other nuclear receptors with transrepression activity may be useful targets for reducing endothelial dysfunction and vascular inflammation in sepsis and septic shock.
用人eNOS(内皮一氧化氮合酶)将单细胞U937细胞转染导致细胞系产生对钙离子载体的一氧化氮(NO),但在静息状态下几乎没有或没有否则(血液,1997年)。 然而,在与佛波尔-12-乙酸13-溶解剂分化后,表达细胞的eNOS通过独立于NO的机制产生了增加的TNFALPHA和活性氧。 N-OMEGA-甲基-L-精氨酸,NOS抑制剂,也没有eNOS的L-精氨酸结合位点的突变(使其无法产生一氧化氮)阻止了eNOS上调TNFALPHA的能力(J Biol Chem,2000年)。相反,与eNOS的NADPH结合位点的超氧化物歧化酶共转染完全阻止了eNOS上调TNFALPHA的产生。最终,ENOS产生的超氧化物被证明可以通过ERK1/2激活上调TNFALPHA(J Biol Chem,2001)。这一系列研究表明,尽管诱导NOS的高输出NO可以增强炎症(J Immunol,1994; J Biol Chem,1997),但ENOS的失调也可以通过基于活性氧的信号转导途径来促进炎症表型。
SP1被证明是通过近端SP启动子结合位点在内皮细胞中调节eNOS的高输出NO的传感器(J Biol Chem,2003)。这项工作定义了一种关键的负面反馈机制,该机制抑制了eNOS并加强了败血性休克中的血管功能障碍。
镰状细胞疾病的特征是脉管系统中的氧化剂和炎症应激,即使没有急性危机(Blood,2004)。镰状细胞疾病中的循环胁迫与血小板中精氨酸代谢异常有关(Pickulation,2007),进一步将这种情况描述为无缺陷状态。
防止慢性血管损伤表型的发展的抗增殖作用与p38 MAPK激活和p21 mRNA稳定有关,随后通过CDE/CHR近代近端启动子降低了Polo样激酶1的调节(BMC Genomics,2005; J Biol Chem,2005; J BMC Genomics; 2005; 2006)。这项调查(见下文)表明,在某些条件下,p38 MAPK可能在脉管系统中起保护作用。
NO和过氧化物酶体增殖物激活的受体(PPAR)都保护内皮并调节其功能。因此,我们使用人脐静脉和杂种EA.HY926内皮细胞在这些信号通路之间进行了串扰(Faseb J,2007)。 ppargamma通过p38 MAPK依赖性信号转导途径激活了ppargamma。这种串扰机制可能有助于NO在脉管系统中的抗炎和细胞保护作用。最近的工作表明,p38 MAPK对于噻唑烷二酮(TZDS)(用于治疗2型糖尿病的药物)的最佳PPAR伽玛也是必需的。 像稳态无生产一样,TZD减少了心血管炎症的标记。 总的来说,这些发现表明,PPAR伽玛以及具有反抑制活性的其他核受体可能是减少败血症和败血性休克中内皮功能障碍和血管炎症的有用靶标。
项目成果
期刊论文数量(2)
专著数量(0)
科研奖励数量(0)
会议论文数量(0)
专利数量(0)
Superoxide production and reactive oxygen species signaling by endothelial nitric-oxide synthase.
内皮一氧化氮合酶的超氧化物产生和活性氧信号传导。
- DOI:10.1074/jbc.m000301200
- 发表时间:2000
- 期刊:
- 影响因子:0
- 作者:Wang,W;Wang,S;Yan,L;Madara,P;DelPilarCintron,A;Wesley,RA;Danner,RL
- 通讯作者:Danner,RL
Signaling by eNOS through a superoxide-dependent p42/44 mitogen-activated protein kinase pathway.
eNOS 通过超氧化物依赖性 p42/44 丝裂原激活蛋白激酶途径发出信号。
- DOI:10.1152/ajpcell.2001.281.2.c544
- 发表时间:2001
- 期刊:
- 影响因子:0
- 作者:Wang,W;Wang,S;Nishanian,EV;DelPilarCintron,A;Wesley,RA;Danner,RL
- 通讯作者:Danner,RL
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ROBERT L DANNER其他文献
ROBERT L DANNER的其他文献
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{{ truncateString('ROBERT L DANNER', 18)}}的其他基金
Preclinical and Clinical Investigations in Septic Shock
感染性休克的临床前和临床研究
- 批准号:
7215797 - 财政年份:
- 资助金额:
$ 7.73万 - 项目类别:
Nitric Oxide Regulation of Inflammatory Responses and Gene Expression
一氧化氮调节炎症反应和基因表达
- 批准号:
8952789 - 财政年份:
- 资助金额:
$ 7.73万 - 项目类别:
Functional Genomics of Inflammation and Critical Illness
炎症和危重疾病的功能基因组学
- 批准号:
9549437 - 财政年份:
- 资助金额:
$ 7.73万 - 项目类别:
Preclinical and Clinical Investigations of Severe Infection and Critical Illness
严重感染和危重疾病的临床前和临床研究
- 批准号:
10923694 - 财政年份:
- 资助金额:
$ 7.73万 - 项目类别:
Preclinical and Clinical Investigations in Septic Shock
感染性休克的临床前和临床研究
- 批准号:
7733589 - 财政年份:
- 资助金额:
$ 7.73万 - 项目类别:
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