ATF3对缺血再灌注心肌的多重保护作用及机制研究

Myocardial ischemia reperfusion injury(IRI) seriously affects the clinical efficacy of revascularization of ischemic heart disease. Inflammation, apoptosis and autophagy are the key factors that mediate myocardial IRI. Activating transcription factor 3(ATF3), an early stress response gene, is involved in many pathophysiological processes such as inflammation, apoptosis and autophagy by regulating histone deacetylation and the transcriptional activity of AP-1、CERB、p53 and NF-κB. The preliminary work from our laboratory has showed that overexpression of ATF3 could reduce the release of inflammatory factors, myocardial cell apoptosis and autophagy significantly after myocardial ischemia reperfusion. In addition, our previous studies also indicated that the above mentioned ATF3 related transcription factors played vital roles in myocardial IRI. .In the present study, we will use neonatal rat cardiomyocytes, Atf3-KO mice and Atf3-TG mice as experimental models to explore the protective effect and mechanism of ATF3 on ischemia reperfusion myocardium at the molecular, cellular and animal levels, which would deepen the understanding of the pathogenesis of myocardial IRI and accumulate the experience of gene therapy to myocardial IRI. At the same time, this project might provide a theoretical and experimental basis for the establishment of ATF3 as a new treatment target in myocardial IRI.

心肌缺血再灌注损伤（IRI）是影响缺血心肌再灌注治疗效果的重要因素。炎症反应、细胞凋亡及细胞自噬是介导心肌IRI发生的重要机制。激活转录因子3（ATF3）作为应激早期快反应基因，可通过调控组蛋白去乙酰化水平及AP-1、CERB、p53、NF-κB等转录因子活性，参与炎症、凋亡及自噬等多种病理生理过程。本课题组前期研究发现，过表达ATF3可显著减少缺血再灌注心肌中炎性因子的释放、抑制心肌细胞凋亡及自噬。同时，我们也证实受ATF3调控的上述转录因子参与了心肌IRI的发生发展。本项目将在前期研究的基础上，以乳鼠心肌细胞、心肌细胞特异性敲除ATF3基因的Atf3-KO小鼠及ATF3转基因的Atf3-TG小鼠为研究对象，深入探讨ATF3在心肌IRI发生发展过程中的作用及分子机制，以期深化对心肌IRI发病机制的认识，为确立ATF3作为心肌IRI防治的新靶点提供理论及实验依据。

心肌缺血再灌注损伤（MIRI）是影响缺血心肌再灌注治疗效果的重要因素。炎症反应、细胞凋亡及细胞自噬是介导MIRI发生的重要机制。激活转录因子3（ATF3）作为应激早期快反应基因，可通过调控组蛋白去乙酰化水平及AP-1、CERB、p53、NF-κB等转录因子活性，参与炎症、凋亡及自噬等多种病理生理过程。本课题组通过重组腺病毒下调H9C2心肌细胞和大鼠心肌组织中ATF3的表达：（1）观察正常及高糖环境下，下调ATF3对缺氧/复氧（H/R）诱导的心肌细胞功能的影响；（2）建立大鼠MIRI模型，探讨ATF3通过多途径介导正常大鼠及糖尿病大鼠MIRI的具体分子机制。目前已取得的研究结果如下：（1）腺病毒成功转染H9C2心肌细胞；（2）ATF3与NF-κB及ERK1/2磷酸化水平密切相关；（3）正常环境下，下调ATF3可促进H/R诱导的炎症反应，加重MIRI；（4）高糖环境下，下调ATF3可抑制H/R诱导的细胞凋亡，减轻糖尿病大鼠MIRI。通过本项目的成功实施，进一步阐明了ATF3在不同糖环境下对MIRI的作用及具体分子机制，为以ATF3为靶点的MIRI防治策略提供了重要参考。

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