PREVENTION OF THROMBOSIS IN ANGIOPLASTY INJURED ARTERIES

预防血管成形术损伤动脉中的血栓形成

• 批准号: 2735269
• 负责人: James T. Willerson
• 金额: $ 40.65万
• 依托单位: UNIVERSITY OF TEXAS HLTH SCI CTR HOUSTON
• 依托单位国家: 美国
• 财政年份: 1996
• 资助国家: 美国
• 起止时间: 1996-08-01 至 2001-04-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/2735269
• 关键词: cardiovascular disorder prevention; cellular pathology; coronary artery; disease /disorder model; eicosanoid metabolism; gene therapy; hyperplasia; intraluminal angioplasty; nonhuman therapy evaluation; postoperative complications; prostacyclins; prostaglandin endoperoxide synthase; swine; thrombosis; tissue /cell culture; transfection; vascular endothelium

DESCRIPTION (adapted from the applicant's abstract): Endothelium is endowed with several biologically active molecules to protect vascular integrity and maintain vascular hemostasis. Prostacyclin (PGI2) is one of the important vasoprotective molecules. It inhibits platelet activation and aggregation, suppresses smooth muscle cell activation and migration, and inhibits monocyte activation. It also diminishes vasoconstrictor responses. Reduced local PGI2 synthesis due to endothelial injury may lead to excessive blood and vascular cell activation thereby accelerating thrombosis and neointimal proliferation. Systemic administration of PGI2 to augment local PGI2 concentration has limited success because of undesirable adverse effects. The applicant proposes to test whether local production of PGI2 at a damaged vascular site can be restored by gene transfer of PGI2 synthetic enzymes and the augmented local PGI2 synthesis can protect against vascular thrombosis. Biosynthesis of PGI2 from arachidonic acid (AA) is catalyzed by prostaglandin H synthase (PGHS, also called cyclooxygenase) which converts AA into PGG2 and than PGG2 to PGH2. PGH2 is further converted to PGI2 by prostacyclin synthase (PGIS). In preliminary studies, this group has shown that endothelial cell PGHS-1 levels are augmented by retrovirus- and adenovirus-mediated transfer of human PGHS-1 cDNA which is accompanied by a large increase in PGI2 synthesis. Administration of adenovirus-CMV-PGHS-1 into angioplasty-damaged pig carotid arteries resulted in a 5-fold increase in PGI2 synthesis. To further the investigation of vascular gene transfer, 5 specific aims are proposed: 1) to evaluate the effect of adenovirus-mediated prostaglandin H synthase-1 (PGHS-1) transfer on preventing thrombosis in experimental animal models; 2) to assess the effect of transfer of endothelial prostacyclin synthase (PGIS) alone and in combination with PGHS-1 gene on the extent and duration of PGI2 production in cultures endothelial cells in vitro and on preventing thrombosis in vivo; 3) to determine the effect of PGHS-1 and/or PGIS gene transfer on intimal hyperplasia in experimental animal models; 4) to evaluate non-viral vectors for transferring PGHS-1 and/or PGIS cDNAs for augmenting PGI2 synthesis in vasoprotection; and 5) to use the most effective of the above gene therapies and determine its efficacy in preventing thrombosis and intimal proliferation in atherosclerotic porcine coronary arteries.

描述（改编自申请人的摘要）：内皮细胞是 赋予多种生物活性分子以保护血管 完整性并维持血管止血。 前列环素 (PGI2) 是一种 重要的血管保护分子。 它抑制血小板 活化和聚集，抑制平滑肌细胞活化和 迁移，并抑制单核细胞活化。 也随之减少 血管收缩反应。 由于以下原因减少了局部 PGI2 合成 内皮损伤可能导致血液和血管细胞过多 激活从而加速血栓形成和新内膜增殖。 全身施用 PGI2 以增加局部 PGI2 浓度 由于不良副作用，成功有限。 申请人 建议测试受损血管是否局部产生 PGI2 位点可以通过 PGI2 合成酶的基因转移来恢复 增强局部 PGI2 合成可以预防血管血栓形成。 由花生四烯酸 (AA) 生物合成 PGI2 的催化作用 前列腺素 H 合酶（PGHS，也称为环加氧酶） 将AA转化为PGG2，然后将PGG2转化为PGH2。 PGH2进一步转化 通过前列环素合酶 (PGIS) 转化为 PGI2。 在初步研究中，这 研究小组表明，内皮细胞 PGHS-1 水平通过 逆转录病毒和腺病毒介导的人 PGHS-1 cDNA 转移 伴随着PGI2合成的大量增加。 管理 腺病毒-CMV-PGHS-1进入血管成形术损伤的猪颈动脉 导致 PGI2 合成增加 5 倍。 为进一步 血管基因转移的研究，提出了5个具体目标： 1）评价腺病毒介导的前列腺素H的作用 合成酶-1 (PGHS-1) 转移在实验中预防血栓形成 动物模型； 2）评估内皮细胞转移的效果 单独的前列环素合酶 (PGIS) 和与 PGHS-1 基因组合的 培养内皮细胞中 PGI2 产生的程度和持续时间 体外细胞和体内预防血栓形成； 3）确定 PGHS-1和/或PGIS基因转移对内膜增生的影响 实验动物模型； 4) 评估非病毒载体 转移 PGHS-1 和/或 PGIS cDNA 以增强 PGI2 合成 血管保护； 5) 使用上述基因中最有效的 疗法并确定其预防血栓形成的功效 动脉粥样硬化猪冠状动脉的内膜增殖。

项目成果

Thromboresistance of balloon-injured porcine carotid arteries after local gene transfer of human tissue factor pathway inhibitor.

人组织因子途径抑制剂局部基因转移后球囊损伤的猪颈动脉的血栓抵抗。

• DOI: 10.1161/01.cir.101.3.289
• 发表时间: 2000
• 期刊: Circulation
• 影响因子: 37.8
• 作者: Zoldhelyi,P;McNatt,J;Shelat,HS;Yamamoto,Y;Chen,ZQ;Willerson,JT
• 通讯作者: Willerson,JT

Differential effects of endothelin receptor activation on cyclic flow variations in rat mesenteric arteries.

内皮素受体激活对大鼠肠系膜动脉循环血流变化的不同影响。

• DOI: 10.1161/01.cir.96.10.3641
• 发表时间: 1997
• 期刊: Circulation
• 影响因子: 37.8
• 作者: Fujise,K;Stacy,L;Beck,P;Yeh,ET;Chuang,A;Brock,TA;Willerson,JT
• 通讯作者: Willerson,JT