内质网应激在PM2.5致动脉粥样硬化斑块破裂中的作用及其机制

Recent epidemiological studies have suggested a link between PM2.5 exposure and cardiovascular disease, especially for increase of atherosclerosis (AS) morbidity and mortality. However, the mechanism of AS occurrence and progression pathogenesis mediated by PM2.5 exposure still remains elusive. The sudden rupture of atherosclerotic plaque and the secondary formation of thrombus are the main cause of ACS. It is known that endoplasmic reticulum stress (ERS) signaling pathway related apoptosis plays an important role in the plaque rupture. PM2.5 shows oxidative activity and oxidative stress can regulate ERS, we therefore assume that PM2.5 can promote the instability of atherosclerotic plaque via ERS pathway. Here, we verify this hypothesis by buildup of AS animal model with ApoE-/- mice. We aim to investigate if ERS signaling pathway is activated by PM2.5 exposure and the importance of this pathway in plaque rupture progression. Moreover, the chaperone PBA will be used to selectively reduce the ERS response, and we will observe if this chaperone would alleviate the atherosclerotic plaque progression under PM2.5 exposure. Thus, there is a practical significance to reveal the mechanism of PM2.5 induced plaque rupture and protect AS susceptible organism against effects of haze air pollution.

大量研究证据显示，暴露高浓度PM2.5可导致或加重心血管疾病，尤其是动脉粥样硬化（AS）的发病率和死亡率显著升高。截至目前，PM2.5暴露促进AS病人病情恶化甚至死亡的机制尚未阐明。AS斑块破裂导致的血栓是引发急性冠脉综合征等严重心血管疾病的重要原因。现有研究认为内质网应激（ERS）途径相关的细胞凋亡在As斑块稳定性失衡中发挥重要作用。鉴于PM2.5的氧化胁迫效应以及氧化应激对ERS的调节作用，我们推测PM2.5暴露很可能通过ERS调控AS斑块破裂。本研究拟采用AS动物模型对此假设进行验证。首先将利用载脂蛋白E缺失小鼠构建AS模型，探究PM2.5暴露是否可以激活ERS通路以及该通路在AS斑块破裂中的作用。此外，还将使用分子伴侣药物PBA选择性干预ERS信号通路，观察其对PM2.5暴露所致AS斑块破裂的影响。本研究对揭示PM2.5诱发AS恶化的机制以及保护AS易感人群有重要的现实意义。

空气污染物，特别是粒径小于等于2.5微米的细颗粒物（PM2.5），与心血管疾病的发病率和死亡率密切相关，对于心血管病患者，大气PM2.5暴露更是增大其发病风险。其中大气PM2.5暴露后动脉粥样硬化（AS）斑块稳定性的变化可能是关键环节。本课题利用构建的AS模型小鼠和野生型C57BL/6小鼠，采用气管滴注的方式进行4周的PM2.5干预，通过组织学分析、酶联免疫吸附测定、免疫组化、qRT-PCR以及Western blot等技术，从大气PM2.5对斑块稳定性的影响和系统炎症、氧化应激以及内质网应激（ERS）在该过程中的调控作用两方面探讨PM2.5诱发AS斑块破损的机制。通过我们研究发现：1）AS模型小鼠较C57BL/6小鼠对大气PM2.5致心血管损伤更加敏感；2）PM2.5对AS模型小鼠斑块的发展和稳定性均有影响；3）AS模型小鼠在暴露大气PM2.5后，系统炎症和氧化应激水平均显著升高；4）AS模型小鼠斑块区ERS通路中的关键因子被激活，细胞凋亡水平有所升高。综合上述结果，大气PM2.5暴露会增加斑块的不稳定性，其潜在机制可能与炎症/氧化应激激活ERS进而诱导斑块内细胞凋亡有关。本研究对雾霾天气保护AS易感人群具有重要的现实意义。