CEREBRAL VASCULAR EFFECTS OF DIABETES AND ATHEROSCLEROSIS

糖尿病和动脉粥样硬化对脑血管的影响

基本信息

批准号：
6618771
负责人：
DONALD D HEISTAD
金额：
$ 25.48万
依托单位：
UNIVERSITY OF IOWA
依托单位国家：
美国
项目类别：
财政年份：
2002
资助国家：
美国
起止时间：
2002-06-01 至 2007-05-31
项目状态：
已结题

项目摘要

Diabetes is a major risk factor for stroke. Clinical evidence indicates that diabetes accelerates development of atherosclerosis, but mechanisms that account for this interaction are not clear. The investigators speculate that hypercholesterolemia may exaggerate endothelial dysfunction through increased superoxide in vessels during hyperglycemia. The goal of this project is to examine pathophysiological interactions between hyperglycemia and hypercholesterolemia in carotid and intracranial cerebral arteries. It is likely that hyperglycemia will accelerate development of atherosclerosis in the carotid artery, but because diabetes is also a disease of small vessels, it will be particularly important to examine effects in the cerebral microcirculation. There are 3 major aims. First, studies are proposed to test the hypothesis that hypercholesterolemia augments generation of superoxide and endothelial dysfunction in carotid and cerebral arteries during hyperglycemia. Second, studies are planned to identify the contribution of endothelium, vascular muscle, and adventitia to superoxide in carotid and cerebral arteries during hyperglycemia and hypercholesterolemia. Third, studies are proposed to elucidate enzymatic mechanisms that account for cerebral vascular dysfunction. The investigators propose to test the hypothesis that vascular NADPH oxidase contributes to increased levels of superoxide and, therefore, vascular dysfunction during diabetes and hypercholesterolemia. Studies are planned in carotid and basilar artery of rabbits and mice in vitro, and in carotid artery and cerebral vessels in vivo. Endothelial vasomotor function will be examined, and superoxide in vessels will be studied with lucigenin chemiluminescence, and with laser confocal microscopy. Levels of superoxide dismutase (SOD) and superoxide in the vessel wall will be altered by pharmacological approaches, adenoviral mediated gene transfer of CuZnSOD to different layers of the vessel wall, with a newly made CuZnSOD transgenic mouse targeted to vascular smooth muscle, and with mice lacking functional NADPH oxidase. These studies may provide important insight about mechanisms which produce accelerated cerebral vascular dysfunction during diabetes and hypercholesterolemia.

糖尿病是中风的主要危险因素。临床证据表明，糖尿病会加速动脉粥样硬化的发展，但解释这种相互作用的机制尚不清楚。研究人员推测，高胆固醇血症可能会通过高血糖期间血管中超氧化物的增加而加剧内皮功能障碍。该项目的目标是检查颈动脉和颅内脑动脉中高血糖和高胆固醇血症之间的病理生理学相互作用。高血糖可能会加速颈动脉粥样硬化的发展，但由于糖尿病也是一种小血管疾病，因此检查对脑微循环的影响尤为重要。有3个主要目标。首先，提出研究来检验高胆固醇血症会增加高血糖期间颈动脉和脑动脉中超氧化物的产生和内皮功能障碍的假设。其次，计划进行研究以确定高血糖和高胆固醇血症期间内皮、血管肌肉和外膜对颈动脉和脑动脉中的超氧化物的贡献。第三，建议进行研究以阐明导致脑血管功能障碍的酶机制。研究人员提议检验以下假设：血管 NADPH 氧化酶会导致超氧化物水平升高，从而导致糖尿病和高胆固醇血症期间的血管功能障碍。计划对兔和小鼠的颈动脉和基底动脉进行体外研究，以及对颈动脉和脑血管进行体内研究。将检查内皮血管舒缩功能，并用光泽精化学发光和激光共聚焦显微镜研究血管中的超氧化物。血管壁中超氧化物歧化酶（SOD）和超氧化物的水平将通过药理学方法、腺病毒介导的 CuZnSOD 基因转移到血管壁的不同层、新制作的 CuZnSOD 转基因小鼠靶向血管平滑肌以及小鼠来改变。缺乏功能性 NADPH 氧化酶。这些研究可能为糖尿病和高胆固醇血症期间加速脑血管功能障碍的机制提供重要见解。