HIV-1 Infection and Endothelial t-PA Release

描述(申请人提供)：心血管疾病是人类免疫缺陷病毒(HIV)-1感染的成年人中出现的一个新问题。事实上，感染HIV-1的人是患动脉粥样硬化性血栓性血管疾病的最快速增长的人群之一。HIV-1血清阳性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高于普通人群。HIV-1感染导致心血管风险升高的机制尚不完全清楚。纤溶功能受损被认为在动脉粥样硬化性血栓性血管疾病的发生和发展中起着核心作用，并与HIV-1感染有关。然而，HIV-1感染导致明显的纤溶低下状态的潜在机制还不是很清楚。目前尚不清楚HIV-1感染者血管内皮细胞释放组织型纤溶酶原激活物(t-PA)的能力是否受损。这一点非常重要，因为决定内源性溶栓潜力的是t-PA局部内皮释放速率，t-PA是启动纤溶的关键酶，而不是循环中的血浆纤溶浓度。因此，本提案的具体目的将是确定：1)HIV-1血清阳性治疗后，血管内皮细胞释放t-PA的能力是否降低；2)HIV-1感染时内皮细胞t-PA释放减少是否与氧化应激增加有关；以及3)HIV-1感染后内皮细胞t-PA释放减少是否与全身炎症有关。为了实现这些目标，将研究年龄在21-50岁之间的艾滋病毒-1血清阴性和未经治疗的艾滋病毒-1血清阳性成年人。血管内皮细胞局部释放t-PA的能力将在体内评估，以响应臂内注射缓激肽(12.5-50 ng/100毫升组织/分钟)和硝普钠(1.0-4.0毫克/100毫升组织/分钟)。通过前臂血管对每种药物刺激的t-PA净释放/摄取将作为动静脉浓度梯度和前臂血浆流量的乘积来计算。为了确定氧化应激对血管内皮细胞t-PA释放的影响，缓激肽和硝普钠的剂量反应曲线将与抗氧化剂维生素C(12毫克/100毫升组织/分钟)一起重复。还将检测血浆炎症生物标志物和t-PA释放之间的关系。预期的结果应该为观察到在感染HIV-1的成年人中观察到的动脉粥样硬化性血栓血管疾病的额外风险提供机制上的洞察，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。

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.