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

• 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
• 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' -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

 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：几份报道表明，艾滋病毒感染的个体表现出包括动脉粥样硬化（AS）在内的加速血管衰老的迹象。可用的数据表明，与HIV感染相关的免疫失调，使用抗逆转录病毒疗法（CART）并未完全恢复。但是，手推车直接或间接也可能在AS中发挥重要作用。有人建议，在衰老过程中以下四个事件是唤起的关键； 1）端粒（TL）缩短介导的DNA损伤和细胞凋亡，2）血管反应性损害，3）感染和4）肿瘤肿瘤损害（吞噬作用）。在这方面，我们的小组报告说，P90RSK-ERK5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，卡车诱导的P90RSK激活抑制了ERK5转录活性，而CART也提高了SCD40L血浆水平。有趣的是，SCD40L也增加了P90RSK的激活。此外，卡车诱导的P90RSK激活抑制了ERK5转录活性，从而降低了Mφ吞噬作用。最后，我们发现CART通过P90RSK激活导致TL缩短，导致DNA损伤和凋亡。通过释放的细胞成分，包括无细胞DNA（CFDNA）和高迁移率组Box 1（HMGB1），通过释放细胞成分（HMGB1）引起了次应力反应的凋亡和损伤增加。基于上面的基本原理，我们提出了一个以P90RSK激活为中心的新假设，该假设提供了与先前描述的联系，与几种观察结果相结合，表明CART和加速与HIV感染的个体相关联。我们将在对E 50年龄的180个HIV+个体（病毒载荷D50 c/ml）的3年纵向研究中检验这一假设，因此，它们的风险增加了诸如Carotid Intima-Media-Media厚度（CIMT）和Carotid Arter Arter Artery刚度（CAS）之类的可测量变化的风险。年龄，性别和雷诺CVD风险评分将匹配90个HIV控制。我们将评估单核细胞（HMGB1）和等离子体（HMGB1，8-OHDG）中参与者衍生的单核细胞和次应力反应对CART和SCD40L对P90RSK的影响。在动物研究中，我们将进一步定义CART和SCD40L对P90RSK诱导的EC和Mφ加速衰老的灾难性影响。具体目的：目标1。确定较长的HIV感染个体中的慢性暴露于CART和SCD40L的血浆水平是否与P90RSK激活有关，导致单核细胞的衰老增强（降低端粒长度，降低效率效率）以及这些单细胞衰减的测量是否与Athersclerosis（CIMT和CAST）（CIMT和CAST）相关。目的2。确定次应力反应的标记（HMGB1的单核细胞和血浆水平），在纸箱治疗的老年HIV感染个体中的8-羟基-2'-脱氧藻氨酸（8-OHDG）的血浆水平是否与CIMT和CAS的测量结果相关。目的3。为了确定体外和小动物模型，CART和SCD40L对P90RSK激活的因果效应，导致EC和Mφ的细胞衰老，这是基于AS的细胞衰老。