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

 描述：一些报告表明，HIV感染者出现血管老化加速的迹象，包括动脉粥样硬化(AS)。现有数据表明，与HIV感染相关的免疫失调在AS中起着作用，这种免疫失调不能通过联合抗逆转录病毒疗法(CART)完全恢复。然而，CART也可能直接或间接地在AS中发挥重要作用。有人认为，在衰老过程中，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，4)吞噬功能障碍。在这方面，我们的小组已经报道了p90RSK-ERK5模块在内皮(EC)功能障碍中起着关键作用。我们的初步数据显示，CART诱导的p90RSK激活抑制了ERK5的转录活性，CART还增加了sCD40L的血浆水平。有趣的是，sCD40L也增加了p90RSK的激活。此外，CART诱导的p90RSK激活抑制了ERK5的转录活性，从而减少了M-Φ的胞吐作用。最后，我们发现CART通过激活p90RSK导致TL缩短，导致DNA损伤和细胞凋亡。细胞凋亡增加和胞吐功能障碍均通过释放细胞成分，包括无细胞DNA(CfDNA)和高迁移率族蛋白1(HMGB1)，引起二次应激反应。基于以上原理，我们提出了一个以p90RSK激活为中心的新假说，该假说提供了先前未描述的几个观察结果之间的联系，这些观察表明CART与HIV感染者的加速之间存在关联。我们将在一项为期3年的纵向研究中验证这一假设，该研究对180名年龄在50岁的HIV+患者(病毒载量D50c/ml)进行了研究，因此他们在颈动脉内膜-中层厚度(CIMT)和颈动脉僵硬(CAS)等标记物发生可测量变化的风险增加。90名艾滋病毒对照组将在年龄、性别和雷诺兹心血管疾病风险得分方面进行匹配。我们将评估CART和sCD40L对参与者来源的单核细胞中p90RSK以及单核细胞(HMGB1)和血浆(HMGB1，8-OHdG)的次级应激反应的影响。我们将在动物实验中进一步明确CART和sCD40L在p90RSK诱导的EC和MΦ加速老化中的因果作用。目的：1.确定慢性暴露于CART和老年HIV感染者血浆sCD40L水平升高是否与p90RSK激活导致单核细胞老化增强(端粒长度缩短、泡沫化减少)相关，以及这些单核细胞老化指标是否与动脉粥样硬化的标志物(CIMT和CAS)相关。目的2.确定接受CART治疗的老年HIV感染者的次级应激反应标志物(单核细胞和血浆HMGB1水平、血浆8-羟基-2‘-脱氧鸟苷(8-OHdG)水平)是否与CIMT和CAS的测量有关。目的3.在体外和小动物模型中，探讨CART和sCD40L对作为AS基础的EC和M-Φ的p90RSK激活导致细胞老化的因果作用。

 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.