Nitric Oxide-Superoxide in Lipid Induced Vascular Diseas

描述（由申请人提供）：异常内皮依赖性 由于血管中一氧化氮生物利用度降低导致的血管舒张 血管壁是与高脂血症相关的血管疾病的关键成分， 高血压、糖尿病、肥胖症和动脉粥样硬化， 在动脉粥样硬化的发病机制中很重要。虽然有许多 血管壁中NO生物利用度降低的潜在原因， 减少NO生成或增加NO降解，通过与 超氧阴离子可能起关键作用。基因治疗方法 动脉粥样硬化可以包括将基因全身递送至肝脏以治疗 风险因素或局部递送至血管壁以增强NO生物利用度 以增加血流、增强新血管形成或限制细胞增殖 在血管壁上。利用NOS局部递送的基因治疗方法 一氧化氮具有多效性， 在脉管系统中的抗动脉粥样硬化作用。此外，更好的 了解超氧化物在各种血管内皮功能障碍中的作用， 动脉粥样硬化的阶段可能允许超氧化物的治疗作用 歧化酶的过度表达。在本提案中，我们将测试 以下假设a）单个NOS同种型可能具有不同的 改变正常和病变血管反应性的特征 B）腺相关病毒载体可用于转移 NOS基因向血管壁的转移，导致血管的长期改变， 反应性而无炎症和c）NOS的长期过度表达， 高胆固醇血症兔血管壁内皮细胞 依赖性血管舒张和延迟动脉粥样硬化的进展，和d） 通过SOD基因转移增加超氧阴离子的清除可能增加NO 生物利用度和逆转脂质诱导的内皮功能障碍。这些 实验将确定哪种NOS亚型最能改变血管 功能，检查eNOS在细胞中的长期表达的功能效应。 用AAV载体转染兔颈动脉，检测NOS对血管内皮细胞的影响， 过度表达对动脉粥样硬化进展的影响，并阐明 超氧化物在内皮功能障碍发病机制中的作用 动脉粥样硬化

DESCRIPTION (provided by applicant): Abnormal endothelium dependent vasorelaxation due to reduced nitric oxide bioavailability in the blood vessel wall is a key component of vascular disease associated with hyperlipidemia, hypertension, diabetes mellitus, obesity and atherosclerosis and may be important in the pathogenesis of atherosclerosis. While there are many potential causes of decreased NO bioavailability in the blood vessel wall, decreased NO generation or increased NO degradation via interaction with superoxide anions may play a pivotal role. Gene therapy approaches to atherosclerosis may include systemic delivery of genes to the liver to treat risk factors or local delivery to the vessel wall to enhance NO bioavailability to augment blood flow, enhance new vessel formation or limit cell proliferation in the vessel wall. A gene therapy approach utilizing local delivery of NOS gene to the vessel wall has advantages as nitric oxide has pleiotropic anti-atherogenic effects in the vasculature. In addition, a better understanding of the role of superoxide in endothelial dysftinction in various stages of atherosclerosis may allow the therapeutic effects of superoxide dismutase overexpression to be explored. In this proposal we will test the following hypotheses a) individual NOS isoform may have distinct characteristics for altering vascular reactivity in the normal and diseased blood vessel wall, b) adeno-associated virus vectors can be used to transfer the NOS gene to the vascular wall resulting in long term alteration of vascular reactivity without inflammation and c) long term overexpression of NOS in the blood vessel wall of the hypercholesterolemic rabbit will improve endothelium dependent vasorelaxation and delay the progression of atherosclerosis and d) increased scavenging of superoxide via SOD gene transfer may increase NO bioavailability and reverse lipid-induced endothelial dysfunction. These experiments will determine which NOS isoform is best at altering vascular function, examine the functional effect of prolonged expression of eNOS in the rabbit carotid artery using AAV vectors, examine the effect of NOS overexpression on progression of atherosclerosis and elucidate the role of superoxide in the pathogenesis of endothelial dysfunction in various stages of atherosclerosis.