Functional significance of a single nucleotide polymorphism in the gene encoding endothelial nitric oxide synthase

内皮一氧化氮合酶基因编码单核苷酸多态性的功能意义

基本信息

项目摘要

A single nucleotide polymorphism (SNP) within the promoter of the endothelial nitric oxide (NO) synthase (NOS3) gene (T-786C, rs2070744) adversely affects the response of endothelial cells (EC) from CC-genotype individuals to shear stress or the prototypic anti-type 1 T-helper (Th1) cell cytokine interleukin-10. Homozygosity for the C-allele, which occurs in about 12% of Caucasians, is a strong predictor for coronary heart disease, polymyalgia rheumatica or rheumatoid arthritis. In a preceding DFG-funded project, we identified a compensatory mechanism involving manganese-dependent superoxide dismutase that helps to maintain the bioavailability of EC-derived NO. With the shear stress-stimulated release of 15-deoxy-delta12,14-prostaglandin J2 (15d-PGJ2) from CC- but not TT-genotype ECs, we have characterised another compensatory mechanism that may not only support the anti-inflammatory capacity of the CC-genotype ECs but also act as a novel general defence mechanism against chronic inflammation. Moreover, data acquired since then point to a possible epigenetic control of NOS3 expression through chromatin remodelling that may differ in at least two aspects between CC- and TT-genotype ECs. With this proposal we plan to (i) establish that STAT3-guided recruitment of the histone-acetyltransferase p300/CBP and/or the histone-lysine N-methyltransferase SETD7 to the CpG-dinucleotide at position -786 in the NOS3 gene (CC-genotype) and the degree of histone H3 acetylation and/or methylation associated therewith results in a different accessibility, e.g. by STAT3, of the distal NOS3 promoter. Alternatively, p300/CBP may serve as a scaffold coordinating the binding of, e.g. STAT3 to its cis-acting element at position -850 to -842, thereby enabling and/or accelerating trans-activation of the NOS3 gene. Moreover, by (ii) generating the corresponding knock-in mice harbouring the human C- or T-type NOS3 promoter on a disease-susceptible genetic background, we plan to verify that the T-786C SNP of the human NOS3 gene, if present, boosts the development of arteriosclerosis and/or arthritis in these animals. The reason for this complex experimental approach is that instead of the 5'-GGC(T->C)GG-3' motif found in humans the murine Nos3 promoter contains a 5'-GGCCAT-3'motif so that the suspected critical CpG-dinucleotide cannot form. Finally, we plan to (iii) corroborate in an in vitro transmigration model mimicking shear stress conditions at arteriosclerosis predilection sites that the T-786C SNP of the human NOS3 gene differentially affects Th1 and Th17 cell-endothelial cell interaction, respectively, through 15d-PGJ2. Furthermore, we will extend our analysis of the plasma levels of 15d-PGJ2 to patients with rheumatoid arthritis to prove that this prostanoid is both a marker and a pivotal constituent of a novel anti-inflammatory defence mechanism.
内皮一氧化氮(NO)合成酶(NOS3)基因启动子(T-786C, rs2070744)内的单核苷酸多态性(SNP)对cc基因型个体内皮细胞(EC)对剪切应激或原型抗1型t辅助(Th1)细胞因子白介素-10的反应产生不利影响。约12%的白种人存在c等位基因的纯合性,这是冠心病、风湿性多肌痛或类风湿性关节炎的一个强有力的预测指标。在之前dfg资助的一个项目中,我们确定了一种涉及锰依赖性超氧化物歧化酶的补偿机制,该机制有助于维持ec衍生NO的生物利用度。随着剪切应力刺激15-deoxy-delta12,14-前列腺素J2 (15d-PGJ2)从CC-而不是tt -基因型ec中释放,我们发现了另一种代偿机制,它不仅支持CC-基因型ec的抗炎能力,而且还作为一种新的抗慢性炎症的一般防御机制。此外,从那时起获得的数据指出,CC-和tt -基因型ECs之间可能存在至少两个方面的差异,即通过染色质重塑对NOS3表达的表观遗传控制。根据这一建议,我们计划(i)确定STAT3引导的组蛋白乙酰转移酶p300/CBP和/或组蛋白赖氨酸n -甲基转移酶SETD7对NOS3基因(cc基因型)-786位cpg -二核苷酸的募集,以及与之相关的组蛋白H3乙酰化和/或甲基化程度,会导致NOS3远端启动子的不同可及性,例如STAT3。或者,p300/CBP可以作为一个支架,协调STAT3与其位于-850至-842位置的顺式作用元件的结合,从而启用和/或加速NOS3基因的反式激活。此外,通过(ii)产生具有疾病易感遗传背景的人类C型或t型NOS3启动子的相应敲入小鼠,我们计划验证人类NOS3基因的T-786C SNP,如果存在,会促进这些动物动脉硬化和/或关节炎的发展。采用这种复杂的实验方法的原因是,在人类中发现的5‘- ggc (T->C)GG-3’基序中,小鼠Nos3启动子含有5‘- ggccat -3’基序,因此无法形成可疑的关键cpg -二核苷酸。最后,我们计划(iii)在模拟动脉硬化易感部位剪切应力条件的体外迁移模型中证实,人类NOS3基因的T-786C SNP分别通过15d-PGJ2差异地影响Th1和Th17细胞与内皮细胞的相互作用。此外,我们将对类风湿关节炎患者的血浆15d-PGJ2水平进行分析,以证明这种前列腺素既是一种标志物,也是一种新型抗炎防御机制的关键组成部分。

项目成果

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Professor Dr. Markus Hecker, Ph.D.其他文献

Professor Dr. Markus Hecker, Ph.D.的其他文献

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{{ truncateString('Professor Dr. Markus Hecker, Ph.D.', 18)}}的其他基金

Kontrollmechanismen der endothelialen NO-Synthase-Expression
内皮NO合酶表达的控制机制
  • 批准号:
    37149645
  • 财政年份:
    2007
  • 资助金额:
    --
  • 项目类别:
    Research Grants
Expression and function of alpha-importins in vascular smooth muscle cells
α-输入蛋白在血管平滑肌细胞中的表达和功能
  • 批准号:
    5332320
  • 财政年份:
    2001
  • 资助金额:
    --
  • 项目类别:
    Research Grants
Biomechanische Steuerung der Genexpression im Gefäßendothel - Bedeutung reaktiver Sauerstoffspezies
血管内皮基因表达的生物力学控制——活性氧的重要性
  • 批准号:
    5099442
  • 财政年份:
    1998
  • 资助金额:
    --
  • 项目类别:
    Research Grants
Endothelin B-Rezeptor-mediierter Gefäßwandumbau in Arterien und Venen - Molekulare Mechanismen und pathophysiologische Bedeutung
内皮素 B 受体介导的动脉和静脉血管壁重塑 - 分子机制和病理生理学意义
  • 批准号:
    5123958
  • 财政年份:
    1998
  • 资助金额:
    --
  • 项目类别:
    Research Grants
Role of zyxin family members in hypertension-induced arterial remodelling
zyxin家族成员在高血压引起的动脉重塑中的作用
  • 批准号:
    329853703
  • 财政年份:
  • 资助金额:
    --
  • 项目类别:
    Research Grants

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