HIV-1 Infection and Endothelial t-PA Release

HIV-1 感染和内皮 t-PA 释放

• 批准号: 7247817
• 负责人: CHRISTOPHER A DESOUZA
• 金额: $ 20.28万
• 依托单位: UNIVERSITY OF COLORADO
• 依托单位国家: 美国
• 财政年份: 2007
• 资助国家: 美国
• 起止时间: 2007-06-07 至 2009-05-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7247817
• 关键词: Address; Adult; Age; Alteplase; Antioxidants; Arterial Fatty Streak; Ascorbic Acid; Atherosclerosis; Biological Markers; Bradykinin; Cardiovascular Diseases; Cardiovascular system; Development; Disodium Salt Nitroprusside; Dose; Enzymes; Fibrinolysis; Forearm; Future; General Population; HIV; HIV-1; Individual; Infection; Inflammation; Infusion procedures; Link; Myocardial Infarction; Oxidative Stress; Plasma; Play; Population; Range; Rate; Regulation; Research; Risk; Role; Stimulus; Supplementation; Thrombosis; Tissues; Vascular Diseases; Vascular Endothelium; cardiovascular risk factor; cohort; in vivo; insight; prevent; response; restenosis; thrombolysis; uptake

DESCRIPTION (provided by applicant): Cardiovascular disease is an emerging problem in human immunodeficiency virus (HIV)-1-infected adults. Indeed, individuals infected with HIV-1 represent one of the most rapidly growing cohorts with atherothrombotic vascular disease. Rates of atherosclerotic lesion development, myocardial infarction and restenosis are significantly higher in HIV-1-seropositive compared with the general population. The mechanisms responsible for the heightened cardiovascular risk with HIV-1 infection are not completely understood. Impaired fibrinolytic function is recognized to play a central role in the initiation and progression of atherothrombotic vascular disease and has been linked to HIV-1 infection. However, the underlying mechanisms responsible for the apparent hypofibrinolytic state with HIV-1 infection are not well understood. It is currently unknown whether the capacity of the vascular endothelium to release tissue-type plasminogen activator (t-PA) is impaired in HIV- 1-infected adults. This is critically important because it is the local endothelial release rate of t-PA, the key enzyme in initiating fibrinolysis, and not circulating plasma fibrinolytic concentrations that determines endogenous thrombolysis potential. Accordingly, the specific aims of the present proposal will be to determine: 1) if the capacity of the vascular endothelium to release t-PA is reduced in HIV-1-seropositive treatment na¿ve adult humans; 2) if the postulated decrease in endothelial t-PA release with HIV-1 infection is due to increased oxidative stress; and 3) if the postulated decrease in endothelial t-PA release with HIV-1 infection is associated with is associated with systemic inflammation. To address these aims, HIV-1-seronegative and untreated HIV- 1-seropositive adults ranging in age from 21-50 years will be studied. Capacity of the vascular endothelium to locally release t-PA will be assessed, in vivo, in response to intrabrachial infusions of bradykinin (12.5-50 ng/100 mL tissue/min) and sodium nitroprusside (1.0-4.0 ¿g/100 ml tissue/min). Net release/uptake of t-PA across the forearm vasculature to each pharmacological stimulus will be calculated as the product of the arteriovenous concentration gradient and forearm plasma flow. To determine the effects of oxidative stress on endothelial t-PA release, the bradykinin and sodium nitroprusside dose response curves will be repeated with a co-infusion of the antioxidant vitamin C (12 mg/100 mL tissue/min). The relation between plasma biomarkers of inflammation and t-PA release will also be examined. The expected results should provide mechanistic insight into the excess risk of atherothrombotic vascular disease observed in HIV-1 infected adults, and experimental support for future antioxidant supplementation trials aimed at reducing/preventing cardiovascular complications associated with HIV-1 infection.

描述（由申请人提供）：心血管疾病是人类免疫缺陷病毒(HIV)-1感染成人的新问题。事实上，感染HIV-1的个体是动脉粥样硬化血栓性血管疾病增长最快的群体之一。与普通人群相比，hiv -1血清阳性患者的动脉粥样硬化病变发展、心肌梗死和再狭窄的发生率明显更高。HIV-1感染导致心血管风险增加的机制尚不完全清楚。纤维蛋白溶解功能受损被认为在动脉粥样硬化血栓性血管疾病的发生和发展中起核心作用，并与HIV-1感染有关。然而，HIV-1感染导致明显的低纤溶状态的潜在机制尚不清楚。目前尚不清楚HIV- 1感染成人血管内皮释放组织型纤溶酶原激活剂（t-PA）的能力是否受损。这一点至关重要，因为决定内源性溶栓潜力的是t-PA的局部内皮释放率，而不是循环血浆纤维蛋白溶解浓度。t-PA是启动纤维蛋白溶解的关键酶。因此，本提案的具体目的将是确定：1)如果血管内皮释放t-PA的能力在hiv -1血清阳性治疗的成年人中减少；2)如果假设的内皮细胞t-PA释放减少与HIV-1感染是由于氧化应激增加；3)假设的内皮细胞t-PA释放减少与HIV-1感染是否与全身性炎症有关。为了实现这些目标，将对年龄在21-50岁之间的HIV-1血清阴性和未经治疗的HIV-1血清阳性成人进行研究。血管内皮局部释放t-PA的能力将被评估，在体内，响应臂内输注缓动素（12.5-50 ng/100 mL组织/分钟）和硝普钠（1.0-4.0¿g/100 mL组织/分钟）。通过前臂血管对每种药物刺激的t-PA净释放/摄取将被计算为动静脉浓度梯度和前臂血浆流量的乘积。为了确定氧化应激对内皮细胞t-PA释放的影响，在共输注抗氧化剂维生素C （12 mg/100 mL组织/min）的情况下，重复慢激肽和硝普钠的剂量反应曲线。血浆炎症生物标志物与t-PA释放之间的关系也将被检查。预期的结果将为在HIV-1感染的成年人中观察到的动脉粥样硬化血栓性血管疾病的过度风险提供机制见解，并为未来旨在减少/预防与HIV-1感染相关的心血管并发症的抗氧化剂补充试验提供实验支持。