Strategies to improve hemorheology and clinical outcome of sickle cell anemia patients by red blood cell derived nitric oxide

利用红细胞源性一氧化氮改善镰状细胞性贫血患者血液流变学和临床结果的策略

• 批准号: 280684238
• 负责人: Dr. Marijke Grau
• 金额: --
• 依托单位: Centre de Recherche de lInstitut du Cerveau et de la Moëlle épinière
• 依托单位国家: 德国
• 项目类别: Research Grants
• 财政年份: 2015
• 资助国家: 德国
• 起止时间: 2014-12-31 至 2018-12-31
• 项目状态: 已结题
• 来源: https://gepris.dfg.de/gepris/projekt/280684238?language=en
• 关键词: Strategies; improve; hemorheology; clinical; outcome

In recent years we have shown that red blood cell nitric oxide synthase (RBC-NOS) produced nitric oxide (NO) is of particular importance to maintain and regulate RBC deformability. Part of this RBC-NOS derived NO is further oxidized to nitrite to function as NO reserve. Other part of the NO binds to RBC proteins, such as a- und ß-spectrin, thus promoting the stabilization of the RBC cyto-skeleton, which positively affects RBC deformability. Sickle cell anemia (SCA) patients show im-paired blood rheology characterized by a severe reduction in RBC deformability, a high rate of hemolysis and enhanced eryptosis. In collaboration with the research group of Prof. Philippe Connes we were able to show that, against expectation, NO production in RBC of SCA patients is increased compared to healthy controls. This is caused by higher activation of the Akt kinase pathway, which consequently increases RBC-NOS activation. The produced NO binds to proteins of the cytoskeleton, most likely a- und ß- spectrin but RBC deformability is still significantly reduced in these patients. To investigate this phenomenon and to develop strategies to improve hemorheology and to reduce clinical complications, we defined the following objectives for this project proposal: 1. Elucidation of hemorheological changes in SCA patients by in vivo investigations of the RBC-NOS and Akt signaling pathway: Relationship between hemorheology, RBC-NOS profile and clinical se-verity. 2. Improvement of RBC deformability and cell integrity, key factors of the known clinical complica-tions, through in vitro modulation of RBC-NOS dependent and independent NO production. Rela-tionship between RBC-NOS derived NO, oxidative/nitrosative stress and RBC deformability. 3. Improvement of RBC deformability and cell integrity by in vitro modulation of intra-erythrocytic NO content by applied shear stress: Pre-investigation of subsequent in vivo exercise intervention. 4. Improvement of NO formation in RBC with subsequent increase in RBC deformability by in vivo exercise intervention. 5. Effects of pharmacological increase in systemic NO content in murine SCA models under base-line conditions and during vaso-occlusive events.

近年来，我们发现红细胞一氧化氮合酶（RBC- nos）产生的一氧化氮（NO）在维持和调节红细胞变形能力方面具有特别重要的作用。部分RBC-NOS衍生的NO进一步氧化为亚硝酸盐，作为NO储备。NO的另一部分与RBC蛋白结合，如a- und ß-spectrin，从而促进RBC细胞骨架的稳定，这对RBC的可变形性有积极影响。镰状细胞性贫血（SCA）患者表现出血液流变学缺陷，其特征是红细胞变形能力严重降低，溶血率高，红细胞增多。与Philippe Connes教授的研究小组合作，我们能够证明，与预期相反，SCA患者红细胞中的NO生成比健康对照组增加。这是由于Akt激酶通路的高度激活，从而增加了RBC-NOS的激活。产生的NO与细胞骨架蛋白结合，很可能是一种β - β -谱蛋白，但在这些患者中RBC的变形能力仍然显著降低。为了研究这一现象并制定改善血液流变学和减少临床并发症的策略，我们为本项目提案确定了以下目标：通过体内研究红细胞- nos和Akt信号通路阐明SCA患者血液流变学变化：血液流变学、红细胞- nos谱与临床真实性的关系2. 通过体外调节红细胞- nos依赖和独立NO生成，改善红细胞变形能力和细胞完整性，这是已知临床并发症的关键因素。红细胞- nos衍生NO、氧化/亚硝化应激与红细胞变形能力的关系3. 通过施加剪应力体外调节红细胞内NO含量改善红细胞变形能力和细胞完整性：随后体内运动干预的预研究。4. 体内运动干预对红细胞NO形成的改善及随后红细胞变形能力的增加。5. 在基线条件下和血管闭塞事件期间，药物增加小鼠SCA模型中全身NO含量的影响。

项目成果

Impact of A Six Week Training Program on Ventilatory Efficiency, Red Blood Cell Rheological Parameters and Red Blood Cell Nitric Oxide Signaling in Young Sickle Cell Anemia Patients: A Pilot Study

• DOI: 10.3390/jcm8122155
• 发表时间: 2019-12-01
• 期刊: JOURNAL OF CLINICAL MEDICINE
• 影响因子: 3.9
• 作者: Grau, Marijke;Nader, Elie;Connes, Philippe
• 通讯作者: Connes, Philippe

Effect of acute exercise on RBC deformability and RBC nitric oxide synthase signalling pathway in young sickle cell anaemia patients

• DOI: 10.1038/s41598-019-48364-1
• 发表时间: 2019-08-14
• 期刊: SCIENTIFIC REPORTS
• 影响因子: 4.6
• 作者: Grau, Marijke;Jerke, Max;Prokop, Aram
• 通讯作者: Prokop, Aram

Red blood cell nitric oxide synthase modulates red blood cell deformability in sickle cell anemia.

• DOI: 10.3233/ch-162042
• 发表时间: 2016
• 期刊: Clinical hemorheology and microcirculation
• 影响因子: 2.1
• 作者: A. Mozar;P. Connes;Bianca Collins;M. Hardy-Dessources;M. Romana;Nathalie Lemonne;W. Bloch;M. Grau