PAR 13-233 cART accelerates vascular aging in HIV infected subjects

 描述：一些报告表明，艾滋病毒感染的个人目前的迹象，加速血管老化，包括动脉粥样硬化（AS）。现有的数据表明，与HIV感染相关的免疫失调，不能通过使用联合抗逆转录病毒治疗（cART）完全恢复，在AS中发挥作用。然而，cART也可能直接或间接地在AS中发挥重要作用。已经表明，在衰老过程中的以下四个事件是诱发AS的关键：1）端粒（TL）缩短介导的DNA损伤和凋亡，2）血管反应性受损，3）炎症，和4）吞噬作用（吞噬作用）受损。在这方面，我们的小组已经报道，p90 RSK-ERK 5模块在内皮（EC）功能障碍中起着至关重要的作用。我们的初步数据表明，cART诱导的p90 RSK激活抑制ERK 5的转录活性和cART也增加sCD 40 L血浆水平。有趣的是，sCD 40 L也增加p90 RSK的活化。此外，cART诱导的p90 RSK活化抑制ERK 5转录活性，从而减少MΦ细胞增多。最后，我们发现cART通过激活p90 RSK引起TL缩短，导致DNA损伤和凋亡。细胞凋亡的增加和红细胞增多症的损害都通过释放细胞成分（包括游离DNA（cfDNA）和高迁移率族蛋白1（HMGB 1））引起继发性应激反应。基于上述基本原理，我们提出了一个新的假设，p90 RSK激活为中心，提供了一个链接，以前没有描述，几个观察结果表明之间的关联cART和加速AS在HIV感染的个人。我们将在一项为期3年的纵向研究中对180名年龄在50岁以上的HIV阳性个体（病毒载量d50 c/ml）进行检验，这些个体因此在AS标志物（如颈动脉内膜中层厚度（CIMT）和颈动脉僵硬度（CAS））中发生可测量变化的风险增加。90名HIV对照者的年龄、性别和Reynolds CVD风险评分匹配。我们将评估cART和sCD 40 L对参与者来源的单核细胞中p90 RSK以及单核细胞（HMGB 1）和血浆（HMGB 1，8-OHdG）中继发性应激反应的影响。我们将在动物研究中进一步确定cART和sCD 40 L对p90 RSK诱导的EC和MΦ加速老化的因果关系。具体目标：目标1。确定老年HIV感染者长期暴露于cART和血浆sCD 40 L水平升高是否与p90 RSK激活相关，导致单核细胞老化增强（端粒长度缩短，单核细胞增多症减少），以及这些单核细胞老化指标是否与动脉粥样硬化标志物（CIMT和CAS）相关。AIM 2.确定接受cART治疗的老年HIV感染者的继发性应激反应标志物（单核细胞和血浆HMGB 1水平、血浆8-羟基-2 '-脱氧鸟苷（8-OHdG）水平）是否与CIMT和CAS指标相关。AIM 3.为了在体外和小动物模型中确定cART和sCD 40 L对p90 RSK活化的因果作用，从而导致AS的基础EC和MΦ的细胞老化。

 DESCRIPTION: Several reports suggest that HIV infected individuals present signs of accelerated vascular aging including atherosclerosis (AS). Available data suggest that the immune dysregualtion associated with HIV infection, not completely restored by the use of combination antiretroviral therapy (cART), plays a role in AS. However, cART directly or indirectly may also play an important role in AS. It has been suggested that the following four events during the aging process are key to evoke AS; 1) Telomere (TL) shortening-mediated DNA damage and apoptosis, 2) impairment of vascular reactivity, 3) inflammation, and 4) impairment of efferocytosis (phagocytosis). In this regard, our group has reported that p90RSK-ERK5 module plays a crucial role in endothelial (EC) dysfunction. Our preliminary data show that cART-induced p90RSK activation inhibited ERK5 transcriptional activity and cART also increased sCD40L plasma levels. Interestingly, sCD40L also increase the activation of p90RSK. Furthermore cART-induced p90RSK activation inhibited ERK5 transcriptional activity thus decreased MΦ efferocytosis. Lastly, we found that cART caused TL shortening via p90RSK activation, leading to DNA damage and apoptosis. Both increased apoptosis and impairment of efferocytosis evoke secondary stress responses via releasing cellular components including cell-free DNA (cfDNA) and high mobility group box 1 (HMGB1). Based on the rationale above, we propose a novel hypothesis centered on p90RSK activation which provides a link, not previously described, to several observations suggesting an association between cART and accelerated AS in HIV infected individuals. We will test this hypothesis in a 3- year longitudinal study of 180 HIV+ individuals (viral load d50 c/ml) aged e 50 years who are therefore at increased risk of developing measurable changes in markers of AS such as carotid intima-media thickness (CIMT) and carotid artery stiffness (CAS). 90 HIV- controls will be matched for age, gender and Reynolds CVD risk score. We will assess the effect of cART and sCD40L on p90RSK in participants-derived monocytes and secondary stress responses both in monocytes (HMGB1) and plasma (HMGB1, 8-OHdG). We will further define the causal effect of cART and sCD40L on p90RSK-induced accelerated aging of EC and MΦ in animal studies. Specific Aims: AIM 1. To determine whether chronic exposure to cART and elevated plasma levels of sCD40L in older HIV infected individuals are associated with p90RSK activation leading to enhanced aging of monocytes (reduce telomere length, reduced efferocytosis) and whether these measures of monocyte aging are associated with markers of atherosclerosis (CIMT and CAS). AIM 2. To determine whether the markers of secondary stress response (monocytic and plasma levels of HMGB1, plasma levels of 8-hydroxy-2'- deoxyguanosine (8-OHdG)) in cART-treated older HIV infected individuals are associated with measures of CIMT and CAS. AIM 3. To determine in vitro and in small animal models, the causal effect of cART and sCD40L on p90RSK activation leading to cellular aging of EC and MΦ which underlie AS.