NITRIC OXIDE/SUPEROXIDE IN LIPID VASCULAR DISEASE

一氧化氮/超氧化物在脂质血管疾病中的作用

• 批准号: 6151347
• 负责人: TIMOTHY O'BRIEN
• 金额: $ 10.02万
• 依托单位: MAYO CLINIC ROCHESTER
• 依托单位国家: 美国
• 财政年份: 1998
• 资助国家: 美国
• 起止时间: 1998-02-05 至 2002-01-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/6151347
• 关键词: Adenoviridae; acetylcholine; anions; atherosclerosis; calcium flux; carotid artery; cyclic GMP; enzyme activity; gene expression; guanylate cyclase; hypercholesterolemia; ionophores; isozymes; laboratory rabbit; nitric oxide; nitric oxide synthase; superoxide dismutase; superoxides; transfection /expression vector; vascular endothelium; vasomotion

DESCRIPTION (Adapted from Investigator's Abstract): Atherosclerosis is a leading cause of death in the Western world, and hypercholesterolemia is a well-known risk factor for its development. Vasomotor abnormalities, in part due to hypercholesterolemia, are present prior to the onset of overt atherosclerosis and might play a role in disease progression. The role of nitric oxide (NO) and superoxide anion in cholesterol-induced vasomotor dysfunction and atherosclerosis is unclear. NO is generated in the endothelium by eNOS and can be inactivated with superoxide anions. Superoxide anions are scavenged by SOD. This project was designed to determine the role of NO and superoxide in cholesterol-induced vasomotor dysfunction by overexpressing the genes for eNOS, CuZnSOD and MnSOD in hypercholesterolemic rabbits. This project is designed to determine the role of endothelial nitric oxide synthase (eNOS) and superoxide dismutase (SOD) in cholesterol-induced vasomotor dysfunction by overexpressing the genes for endothelial eNOS, copper zinc superoxide dismutase (CuZnSOD)and manganese superoxide dismutase (MnSOD) in the hypercholesterolemic rabbit carotid artery. The long term goal of this research is to examine the role of NO and superoxide anion in atherogenesis. eNOS and SOD overexpression (both isoforms) in the arterial wall of rabbits will be achieved in vivo using gene transfer with adenoviral vectors. Cholesterol-induced vasomotor dysfunction will be compared in animals treated with vectors expressing eNOS and/or SOD and controls. Results from these studies should provide fundamental information about the roles of NO and superoxide anions in cholesterol-induced vasomotor dysfunction, and the data might provide useful information for the development of gene therapy-based strategies for the treatment of this disorder. The long-term goal of this research is to examine the role of NO and SOD in atherogenesis. eNOS and SOD overexpression in arteries will be done in vivo using a gene transfer technology that employs adenoviral vectors. Cholesterol-induced vasomotor dysfunction will be compared in animals treated with vectors expressing eNOS and/or SOD and controls. Specific Aim 1 is to determine the role of eNOS in cholesterol-induced vasomotor dysfunction. It is hypothesized that NOS activity and cGMP levels are reduced in atherosclerotic-induced vasomotor dysfunction and that restoration of eNOS activity and cGMP levels improves vasomotor responses. Specific Aim 2 is to determine if SOD is an important regulator of vasomotor tone. It is hypothesized that adenoviral vectors of SOD attenuate cholesterol-induced vasomotor dysfunction, and that CuMnSOD is the most active of the two SOD isoforms. Specific Aim 3 is to determine the relative roles of eNOS and SOD in cholesterol-induced vasomotor dysfunction. It is hypothesized that co-expression of SOD with eNOS will augment vascular relaxation.

描述（改编自研究者摘要）：动脉粥样硬化是一种疾病

项目成果

Transfer and expression of recombinant nitric oxide synthase genes in the cardiovascular system.

重组一氧化氮合酶基因在心血管系统中的转移和表达。

• DOI: 10.1016/s0165-6147(98)01190-0
• 发表时间: 1998
• 期刊: Trends in pharmacological sciences
• 影响因子: 13.8
• 作者: Chen,AF;O'Brien,T;Katusic,ZS
• 通讯作者: Katusic,ZS

Adenoviral-mediated overexpression of catalase inhibits endothelial cell proliferation.

• DOI: 10.1152/ajpheart.00358.2001
• 发表时间: 2002-12
• 期刊: American journal of physiology. Heart and circulatory physiology
• 作者: M. Zanetti;Z. Katusic;T. O’Brien

Gene transfer of endothelial nitric oxide synthase alters endothelium-dependent relaxations in aortas from diabetic rabbits.

内皮一氧化氮合酶的基因转移改变糖尿病兔主动脉内皮依赖性松弛。

• DOI: 10.1007/s001250050052
• 发表时间: 2000
• 期刊: Diabetologia
• 影响因子: 8.2
• 作者: Zanetti,M;Sato,J;Katusic,ZS;O'Brien,T
• 通讯作者: O'Brien,T

In vivo gene transfer of inducible nitric oxide synthase to carotid arteries from hypercholesterolemic rabbits.

诱导型一氧化氮合酶体内基因转移至高胆固醇血症兔的颈动脉。

• DOI: 10.1161/01.str.0000068366.00173.e7
• 发表时间: 2003
• 期刊: Stroke
• 影响因子: 8.3
• 作者: Zanetti,Michela;d'Uscio,LiviusV;Kovesdi,Imre;Katusic,ZvonimirS;O'Brien,Timothy
• 通讯作者: O'Brien,Timothy

Recombinant gene transfer of endothelial nitric oxide synthase augments coronary artery relaxations during hypoxia.

内皮一氧化氮合酶的重组基因转移可增强缺氧期间冠状动脉的松弛。

• DOI: 10.1161/01.cir.100.suppl_2.ii-335
• 发表时间: 1999
• 期刊: Circulation
• 影响因子: 37.8
• 作者: Cable,DG;Pompili,VJ;O'Brien,T;Schaff,HV
• 通讯作者: Schaff,HV