PLATELET-DERIVED NITRIC OXIDE AND HEMOSTASIS

血小板源性一氧化氮和止血

• 批准号: 6390275
• 负责人: JANE E Freedman
• 金额: $ 2.74万
• 依托单位: GEORGETOWN UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2000
• 资助国家: 美国
• 起止时间: 2000-07-01 至 2001-09-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/6390275
• 关键词: enzyme activity; genetically modified animals; hemostasis; human subject; laboratory mouse; nitric oxide; nitric oxide synthase; oxidative stress; platelet activation; protein kinase C; thiols; thrombosis; tocopherols

DESCRIPTION (Adapted from Investigator's Abstract): Vessel injury and thrombus formation are the cause of most ischemic coronary syndromes. In this setting, platelet activation at the site of disrupted plaque leads to the recruitment of additional platelets and the evolution of the platelet-rich thrombus. In addition, patients with coronary atherosclerosis have impaired effective release of endothelial nitric oxide (NO), a known vasodilator and inhibitor of platelet function. While constitutive nitric oxide synthase (cNOS) has been identified in human platelets and megakaryoblastic cells and activated platelets elaborate NO, the role of platelet-derived NO in hemostasis has not been defined. Preliminary data demonstrates that stimulated platelets produce NO which inhibits recruitment and is present in decreased levels in patients with unstable coronary syndromes. The central hypothesis of this proposal is that the regulation of platelet-derived NO release alters platelet function, modulates vascular hemostasis, and influences the development of platelet-mediated thrombosis. To test this hypothesis, the following specific aims are proposed: 1) To further define the contribution of platelet-derived NO to platelet recruitment and determine its role in hemostasis and thrombosis in vivo using a genetic model of NO synthase deficiency. Using an existing genetic murine model of cNOS deficiency (targeted disruption of nitric oxide synthase isoform 3 (NOS3) gene), the significance of platelet-NO production will be explored at the molecular level; 2) To determine the biochemical and molecular mechanism(s) that regulate platelet-derived NO release. Preliminary data indicate that inhibition of PKC leads to enhanced release of platelet-derived NO. The interaction between this cell signaling pathway and platelet NO regulation will be examined; and 3) To characterize clinically relevant variables that influence the release of platelet-derived NO and determine the biochemical and molecular mechanism(s) responsible for these observations. In preliminary data, it has been shown that alpha-tocopherol and thiol levels (a measure of redox status) are independent predictors of platelet-derived NO in patients with unstable coronary syndromes. The effect of these antioxidants on platelet NO release and cNOS expression will be determined. Therefore, this proposal will study biochemical and molecular mechanism(s) by which platelet-derived NO influences hemostasis and may suggest a unique mechanism by which a platelet product modulates thrombosis and influences the manifestations of cardiovascular disease.

描述（改编自研究者摘要）：血管损伤和血栓