HIV-1 Infection and Endothelial t-PA Release

描述（由申请方提供）：心血管疾病是人类免疫缺陷病毒（HIV）-1感染成人的一种新问题。事实上，感染HIV-1的个体是动脉粥样硬化血栓形成性血管疾病中增长最快的群体之一。与普通人群相比，HIV-1血清阳性患者动脉粥样硬化病变发展、心肌梗死和再狭窄的发生率明显较高。HIV-1感染导致心血管风险升高的机制尚未完全了解。纤溶功能受损被认为在动脉粥样硬化血栓形成性血管疾病的发生和发展中起着重要作用，并与HIV-1感染有关。然而，对HIV-1感染引起的明显纤溶功能低下状态的潜在机制还不清楚。目前尚不清楚HIV- 1感染成人的血管内皮释放组织型纤溶酶原激活物（t-PA）的能力是否受损。这是非常重要的，因为决定内源性溶栓潜力的是t-PA的局部内皮释放速率，t-PA是启动纤溶的关键酶，而不是循环血浆纤溶浓度。因此，本提案的具体目的是确定：1）在未接受过HIV-1血清阳性治疗的成年人中，血管内皮释放t-PA的能力是否降低; 2）假设的HIV-1感染时内皮t-PA释放的降低是否是由于氧化应激增加;和3）如果假设的内皮t-PA释放减少与HIV-1感染有关，则与全身炎症有关。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。将在体内评估血管内皮局部释放t-PA的能力，以响应缓激肽（12.5-50 ng/100 mL组织/min）和硝普钠（1.0-4.0 μ g/100 mL组织/min）的肱动脉内输注。每种药理学刺激的前臂血管系统中t-PA的净释放/摄取将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t-PA释放的影响，将使用抗氧化剂维生素C（12 mg/100 mL组织/min）的共输注重复缓激肽和硝普钠剂量反应曲线。还将检查炎症的血浆生物标志物与t-PA释放之间的关系。预期的结果应该提供机制的洞察到的过度风险的动脉粥样硬化血栓形成性血管疾病观察到的HIV-1感染的成年人，并为未来的抗氧化剂补充试验，旨在减少/预防与HIV-1感染相关的心血管并发症的实验支持。

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.