大气细颗粒物金属组分调控ACE2-Ang(1-7)-Mas轴影响血压的机制研究

Fine particle (PM2.5) has been proven to be related with hypertension or even myocardial infarction, with its metal components being the major pathogenic substances. Researches have shown that PM2.5 increases both ACE and AngII expression levels in rat. However, the impact of PM2.5 on the ACE2-Ang(1-7)-Mas axis, which is an essential part to maintain stable blood pressure, is still not clear. We have found that water soluble components of PM2.5 downregulate ACE2 and Ang (1-7) expression in vascular endothelial cells. Therefore, our current project aims to: 1) establish a hypertensive emergency prospective cohort in 2013-2014. We will collect data from daily hospital emergency department visits of hypertension (ICD-10: I10) in the Third Xiangya Hospital of Central South University and analyze the levels of the 17 metal components of PM2.5. The conditional logistic regression model will be used to evaluate the associations between hypertensive emergency and fine particle metal components levels; 2) SHR (n=30) will be exposed to PM2.5 from different season by daily intra-tracheal instillation for three consecutive days, and the effects of metal components of PM2.5 on blood pressure, regulation of ACE2, Ang (1-7), and Mas receptor expression in heart and blood vessels of SHR will be analyzed; 3) SHR (n=170) treated with XNT (ACE2 agonist) or DX600 (ACE2 antagonist) will be exposed to three different metal sulfates whose concentrations are among the highest in PM2.5. Studies on how these metal sulfates regulate the ACE2-Ang (1-7)-Mas axis will help to demonstrate the mechanism of PM2.5 metal components affect blood pressure, and to provide a theoretical basis to clarify the cardiovascular harm of PM2.5.

大气细颗粒物(PM2.5)被证实与高血压甚至心肌梗死相关，金属组分是其主要致病物质。研究显示PM2.5可增加大鼠ACE和AngII表达，但PM2.5对维持血压稳定重要环节ACE2-Ang(1-7)-Mas轴的影响尚不清楚。申请者发现PM2.5水溶性成分可下调血管内皮细胞ACE2、Ang(1-7)表达，拟通过：1)建立2013-2014年高血压急诊前瞻性队列，采用条件Logistic回归模型分析PM2.5金属组分与高血压急诊的关系；2)采用不同季节PM2.5染毒SHR大鼠，探索金属组分变化对大鼠血压及心脏、血管ACE2、Ang(1-7)、Mas受体表达的影响；3)通过ACE2激动剂XNT和拮抗剂DX600干预SHR大鼠，明确3种PM2.5含量较高的金属硫酸盐对大鼠ACE2-Ang(1-7)-Mas轴的调节作用，探索PM2.5金属组分对血压的影响机制，为阐明PM2.5的心血管危害提供理论依据。

国外的流行病学调查提示大气细颗粒物(PM2.5)浓度增高与高血压、心肌梗死等心血管事件发生相关，但我国的PM2.5浓度显著高于欧美国家，且组分和地域分布也存在明显差异，是否存在类似的关联还缺少足够的证据，PM2.5以及其中的化学成分如何影响血压波动的机制则更不清楚。.为了明确PM2.5及其重金属组分与心脑血管急诊的关系，本研究建立了长沙PM2.5与18种组分（Na、Mg、Al、Si、P、S、K、Ca、Ti、Mn、Fe、Ni、Cu、Zn、Pb、V、As和Cr）数据库及心脑血管急诊的临床数据库，采用条件Logistic回归模型和Poisson模型分析了大气污染对心脑血管疾病急诊就医的影响。结果发现PM2.5及Pb、Zn、Ni等重金属元素浓度增高与脑出血急诊入院升高显著相关。对2120例重金属污染区人群的分析也显示，血铅的浓度直接与血压、血尿酸的升高呈正线性相关。同时，我们采用季节分层的双向回顾性病例交叉设计，发现长沙市秋季SO2、NO2、PM10浓度与脑出血和脑梗死急诊均呈正向关联，其中SO2对脑梗死急诊影响更明显。而对心肌梗死数据的分析则发现，PM2.5短期内浓度升高与急性ST段抬高性心肌梗死相关，低温条件下PM2.5的影响更为显著，女性、不吸烟、高血压患者和糖尿病患者是PM2.5急性暴露的易感人群。.为了进一步阐明PM2.5重金属组分调控血压的机制，本研究进一步模拟了PM2.5铅成分、镉成分暴露对内皮细胞和SD大鼠的影响。结果发现与模拟PM2.5铅含量的高浓度硫酸铅短期暴露会导致大鼠舒张压显著增高，卡托普利预处理后可以显著减弱硫酸铅成分对大鼠舒张压的影响。同时RT-PCR和Western Blot结果提示硫酸铅暴露会使大鼠ACE-AngII-AT1R基因的mRNA和蛋白表达显著上调，而对于ACE2-Ang（1-7）-Mas基因表达无影响。对于镉成分的模拟研究也显示，氯化镉可以激活内皮细胞的ACE-AngII-AT1R轴基因和蛋白表达，同时ACE2表达也有上调。.我们的研究提示PM2.5急性暴露可能是通过铅镉等重金属成分过度激活ACE-AngII-AT1R基因导致血压增高，从而增加心血管意外的风险。本研究为PM2.5暴露高风险人群的提前预警提供了理论依据，有助于进一步认识大气PM2.5的环境行为与健康效应。