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

PAR 13-233 cART 加速 HIV 感染者的血管老化

基本信息

批准号：
9066206
负责人：
Jun-Ichi Abe
金额：
$ 73.31万
依托单位：
UNIVERSITY OF ROCHESTER
依托单位国家：
美国
项目类别：
财政年份：
2014
资助国家：
美国
起止时间：
2014-09-15 至 2019-05-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/9066206
关键词：
8-hydroxy-2&apos -deoxyguanosine Advanced Glycosylation End Products Affect Age Aging Aging-Related Process Animal Model Animals Apoptosis Apoptotic Arterial Fatty Streak Atherosclerosis Blood Vessels Cardiovascular Diseases Carotid Arteries Carotid Atherosclerotic Disease Cell Aging Cells Cerebrovascular Disorders Chronic Collection DNA Damage Data Eating Endothelial Cells Event Exposure to Feedback Functional disorder Gender HIV HIV Infections HMGB1 Protein Health Immune Impairment In Vitro Individual Inflammation Inflammatory Intervention Lead Length Lesion Link Longitudinal Studies MAPK7 gene Measurable Measures Mediating Necrosis Opsonin Participant Phagocytosis Phosphorylation Plasma Play Prevention strategy Production Reactive Oxygen Species Regimen Reporting Risk Role Scheme Signal Transduction Telomere Shortening Testing Thrombosis Toll-like receptors Viral Load result aged antiretroviral therapy arterial stiffness base biological adaptation to stress cardiovascular disorder risk cell free DNA indexing intimal medial thickening macrophage monocyte novel premature prevent receptor for advanced glycation endproducts senescence telomere

项目摘要

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.

描述：一些报告表明，HIV 感染者出现血管加速老化的迹象，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（通过联合抗逆转录病毒治疗 (cART) 未能完全恢复）发挥了一定作用。然而，cART 也可能在 AS 中直接或间接发挥重要作用。有人认为，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 损伤和细胞凋亡，2) 血管反应性受损，3) 炎症，4) 胞吞作用（吞噬作用）受损在这方面，我们的小组报道了 p90RSK-ERK5 模块在内皮 (EC) 中发挥着至关重要的作用。我们的初步数据表明，cART 诱导的 p90RSK 激活抑制了 ERK5 转录活性，并且 cART 还增加了 sCD40L 血浆水平。 sCD40L 还增加了 p90RSK 的激活，此外，cART 诱导的 p90RSK 激活抑制了 ERK5 转录活性，从而降低了 MΦ 胞吞作用。最后，我们发现 cART 通过 p90RSK 激活导致 TL 缩短，导致 DNA 损伤和细胞凋亡增加。通过释放细胞成分（包括游离 DNA (cfDNA) 和高迁移率族盒 1 (HMGB1)）来引发二次应激反应。基于上述原理，我们提出了一个以 p90RSK 激活为中心的新假设，该假设提供了先前未描述的与一些观察结果的联系，表明 cART 与 HIV 感染者加速 AS 之间存在关联。我们将在 3 年内对个体进行测试。对 180 名年龄在 50 岁左右的 HIV+ 个体（病毒载量 d50 c/ml）进行的纵向研究，这些人因此出现 AS 标志物发生可测量变化的风险增加，例如颈动脉内膜中层厚度 (CIMT) 和颈动脉僵硬度 (CAS)。将匹配 90 名 HIV 对照者的年龄、性别和雷诺 CVD 风险评分。我们将评估 cART 和 sCD40L 对参与者来源的单核细胞中的 p90RSK 和单核细胞中的继发性应激反应 (HMGB1) 的影响。我们将进一步确定 cART 和 sCD40L 对 p90RSK 诱导的 EC 和细胞加速老化的因果影响。动物研究中的 MΦ 具体目标：目标 1. 确定老年 HIV 感染者长期暴露于 cART 和血浆 sCD40L 水平升高是否与 p90RSK 激活导致单核细胞老化加速（缩短端粒长度、减少胞吞作用）相关，以及是否与 p90RSK 激活相关。这些单核细胞衰老指标与动脉粥样硬化标志物（CIMT 和 CAS）相关。 2. 确定这些标志物是否是继发性应激反应。 cART 治疗的老年 HIV 感染者的单核细胞和血浆水平 HMGB1、血浆 8-羟基-2'-脱氧鸟苷 (8-OHdG) 水平与 CIMT 和 CAS 测量值相关。 AIM 3。在小动物模型中，cART 和 sCD40L 对 p90RSK 激活的因果作用导致导致 AS 基础的 EC 和 MΦ 细胞老化。