环境PM2.5通过PPARɑ介导的心肌能量代谢重构诱导心力衰竭的毒性机制

Epidemiological evidences have shown that PM2.5 is one of the potential factors caused the heart failure. The peroxisome proliferator activated receptors (PPARs)-mediated myocardial metabolism remodeling plays a pivotal role in the occurrence and development of heart failure, but its roles in the toxic mechanisms of PM2.5-induced heart failure have not been reported. Additionally, we had found that atmospheric PM2.5 from Taiyuan city exposure caused the cardiac contractile dysfunction of SD rats and the abnormal expression of PPARɑ. Hence, this project intends to expose SD rats to different doses of PM2.5 from Taiyuan in summer or winter. Then, we test the heart mechanical index in PM2.5-exposed rats, including cardiac contractile function, heart rate and heart rate variability. Moreover, the levels of cardiac energy metabolism are also measured, including transporter and uptake of energetic substrates, activites of key enzymes in energetic metabolism, usage and storage of energy. Lastly, adopting models of myocardial cells with PPARɑ over-expression and SD rats treated with PPARɑ activators, the critical role of PPARɑ in molecular mechanisms of PM2.5-induced heart failure was determined. Accordingly, this study provides potential clues for developing novel strategies for prevention and therapy of heart failure, and offers a scientific basis for the necessity of prevention and control of urban dust-haze.

流行病学调查显示，大气PM2.5是诱发心力衰竭的潜在因素之一。过氧化物酶体增殖物激活受体（PPARs）介导的心肌能量代谢重构在心力衰竭发生发展中起重要调控作用，而目前针对心肌能量代谢重构，研究PM2.5暴露诱发心力衰竭的作用机制尚未见报道。本课题前期研究发现，太原市最高环境浓度PM2.5暴露可引起大鼠心脏收缩功能障碍，且PPARɑ表达异常。因此，本课题拟选择太原市夏季和冬季大气PM2.5作为对象物质，采用不同环境浓度PM2.5对SD大鼠染毒，检测心脏收缩功能、心率和心率变异性等心肌机械力学参数；测定能量底物选择及利用、关键代谢酶活性、能量利用及储存等心肌能量代谢指标；构建PPARɑ过表达的心肌细胞和PPARɑ激活剂诱导的SD大鼠模型，探索PPARɑ在PM2.5暴露致心力衰竭中的关键角色和调控机制。本项目旨在为心力衰竭预防和治疗提供新思路，为城市雾霾防控的必要性提供科学依据。

大气颗粒物的健康风险已引起广泛关注，虽然目前已有流行病学证据表明大气细颗粒物暴露与心力衰竭的发病和死亡有密切关联，但环境浓度大气细颗粒物暴露引发心力衰竭的季节差异效应及毒性机制仍不明确。本项目采集华北重污染地区太原市夏季和冬季大气PM2.5作为代表性颗粒物样本，建立不同季节不同浓度PM2.5染毒的SD大鼠模型，明确PM2.5暴露影响心肌结构和功能变化的季节及剂量效应关系；进一步围绕心力衰竭发生发展中扮演重要角色的心肌能量代谢重构过程，揭示不同季节PM2.5暴露后大鼠心肌能量代谢不同层面的响应变化；基于PPARs家族的中间介导效应，阐明PM2.5暴露通过调控心肌能量代谢重构介导心脏功能紊乱的潜在毒性机制。结果表明，不同季节PM2.5暴露导致大鼠心脏结构损伤和功能障碍，表现为大鼠心肌细胞凋亡比例和脂质过氧化产物丙二醛明显升高，心率和心率变异性下降，血液动力学和超声心动图参数异常变化，且冬季PM2.5毒性效应更明显。不同季节PM2.5暴露引发心肌组织能量代谢重塑，且不同剂量响应效应不同，表现在低剂量PM2.5暴露诱导能量物质ATP生成增加、β氧化和三羧酸循环代谢增强，出现明显的能量代谢代偿效应，而高剂量PM2.5暴露引发ATP水平降低、能量底物脂肪酸和葡萄糖的选择利用改变、关键能量代谢途径失衡。高剂量PM2.5暴露抑制PPARs家族因子表达，且对PPARα效应最显著，PPARα激动剂复合暴露实验显示，PM2.5暴露通过作用PPARα进而抑制脂肪酸转运同时促进葡萄糖转运，引发心肌能量代谢重塑、心肌组织功能紊乱以及结构损伤。本项目明确了大气细颗粒物致心力衰竭的季节和剂量差异效应，为城市雾霾防控及制定相应的环境卫生标准提供科学依据；同时也揭示了大气颗粒物致心肌损伤作用机制以及关键指标，为预防大气颗粒物引起的疾病提供了潜在的新治疗靶点。