LncRNA在多环芳烃暴露致心血管早期损伤的作用与机制

Polycyclic aromatic hydrocarbons (PAHs) exposure could cause early cardiovascular damage or increase the risk of cardiovascular disease, but the underlying mechanisms are largely unknown. Recent studies on a new class of long non-coding RNA, known as LncRNA show their involvement in numerous biological and pathological processes including cardiovascular disease occurrence and development, however, the potential role of LncRNAs was never investigated in the etiology and pathogenesis of early cardiovascular damage caused by PAHs exposure. We will firstly perform a two-stage study in healthy coke oven workers to identify LncRNA associated with PAHs exposures. In the discovery stage, we will select 15 workers with higher PAHs exposure, and 15 matched controls with lower PAHs exposure based on ambient concentrations of total PAHs and urinary monohydroxy-PAHs. For the initial LncRNA screening, LncRNA expression signature in plasma from 15 pair individuals will be performed by Human LncRNA microarray. Using bioinformatic analysis, we will compare LncRNA expression profiles between these two groups and select the promising LncRNA. The selected LncRNA will be validated in 800 workers by real-time PCR. We will evaluate whether there are dose-response relationships of PAHs with LncRNA, LncRNA with markers of oxidative stress and inflammation, LncRNA with heart rate variability (HRV) and silent myocardial ischemia (SMI), as well as their interactions with HRV and SMI. Identified targets of the top/best LncRNA will then be selected for functional assays in cell culture using gain- or loss-of function approaches. The project will provide scientific evidences for further elucidation of the basic mechanisms operating in PAHs-associated early cardiovascular damage that are regulated by LncRNA, and personalized prevention to incorporate epigenetic information to high risk individuals.

多环芳烃（PAHs）污染可导致心血管早期损伤或增加心血管疾病的发生风险，但机制仍不清楚。长链非编码RNA（LncRNA）在心血管疾病的发生发展中起着重要调控作用，然而LncRNA在PAHs暴露致心血管早期损伤的作用和机制研究国内外均未见报道。本项目根据焦化作业环境和尿PAHs代谢物水平，选取15对PAHs高暴露的个体与匹配的对照，采用芯片检测两组血浆LncRNA的表达谱，筛选出特征性差异表达的LncRNA，进一步采用RT-PCR在800例焦化人群中验证。探讨PAHs与LncRNA、LncRNA与氧化应激和炎性因子、LncRNA与心率变异性（HRV）和无症状性心肌缺血（SMI）的剂量反应关系，以及LncRNA与PAHs等的交互作用对HRV和SMI的影响。最具有显著关联的LncRNA将进行功能实验，为阐明LncRNA在PAHs对心血管损伤的早期生物学作用和机制，对高危个体的预防与干预提供依据。

多环芳烃（PAHs）污染可显著增加心血管早期损伤或动脉粥样硬化性心血管疾病（ASCVD）的发生，而长链非编码RNA（LncRNA）在心血管疾病的发生发展中起着重要调控作用，但是LncRNA在PAHs暴露致心血管早期损伤中的作用尚不清楚。本项目依据焦化作业环境和尿PAHs代谢物水平，选取了12对PAHs高暴露的工人与匹配的对照，采用芯片检测两组血浆LncRNA的表达谱，筛选出特征性差异表达的LncRNA，进一步采用数字RT-PCR在403例焦化人群中验证。总人群中NR_024564的表达水平与尿PAHs浓度、心率变异性和ASCVD之间均未发现明显关联，但在吸烟者中发现1-羟基芘（1-OHP）和总PAHs（ΣOH-PAHs）与NR_024564呈剂量-反应的负向关联，而NR_024564与相邻RR间期差值的均方根（RMSSD）和高频功率（HF）之间存在剂量-反应的正向关联，且NR_024564与吸烟、8异前列腺素（8-iso-PGF）对心率变异性有显著的交互作用。同时，高水平的1-OHNa和ΣOH-PAH个体中，NR_024564降低与ASCVD评分风险剂量反应增高有关，且1-OHNa和2-OHNa与NR_024564对ASCVD风险评分的增高有显著交互作用。结果提示NR_024564及其与PAHs、吸烟、8-iso-PG等的交互作用可能是影响PAHs对早期心血管损伤的新机制，为阐明LncRNA在PAHs对心血管损伤的早期生物学作用提供了科学依据。