巨噬细胞COX-2/mPGES-1/PGE2/EP4通路在急性心肌梗死中的作用

急性心肌梗死是心血管疾病致死致残的主要原因，深入探讨心肌梗死和梗死后心室重构发生的分子机制，是防治心肌梗死、延缓慢性心力衰竭的关键所在。前列腺素E2（PGE2）是花生四烯酸的环氧酶代谢产物，其在心血管疾病中的应用备受关注。我们之前的研究发现PGE2合成的关键酶COX-2和mPGES-1在心血管疾病中存在明显的细胞选择性生物学活性，选择性抑制巨噬细胞COX-2或mPGES-1可以延缓动脉粥样硬化和血管损伤的发生发展，但其在心肌梗死中的作用尚未阐明。动脉粥样硬化是急性心肌梗死发生的首要诱因，我们推测选择性抑制巨噬细胞COX-2或mPGES-1也可能改善梗死后的心室重构。本课题将应用多种条件性基因敲除小鼠模型，结合体外细胞实验，特异性抑制剂和siRNA技术，阐明巨噬细胞COX-2/mPGES-1/PGE2/EP4通路在心肌梗死和梗死后心室重构中的作用及其分子机制，为心肌梗死的防治提供新思路。

Acute myocardial infarction (MI) is the most common cause of chronic heart failure and sudden cardiac death. The effects of therapeutic intervention designed to prevent or attenuate myocardial infarction are best considered with reference to the pathophysiological mechanisms of postinfarction cardiac remodeling. Prostaglandin (PG) E2 is an important lipid mediator that regulates diverse and important physiological processes, including inflammation, pain, atherosclerosis and MI. Microsomal PGE2 synthase (mPGES)-1 is upregulated and functionally coupled with Cyclooxygenase (COX)-2 and to mediate PGE2 production during inflammation. We recently reported the cell selective cardiovascular biology of that COX-2 and mPGES-1 that deletion of these enzymes in myeloid cells retarded atherogenesis and attenuated the vascular injury responses; while the vascular cells deletion exhibited opposite effects. Thus selectively targeting macrophage COX-2 or mPGES-1 for inhibition may have preferable cardiovascular efficacy. However, the role of macrophage COX-2, mPGES-1 in myocardial infarction is not clear. Here, we will use mice lacking COX-2 or mPGES-1 in macrophages, to determine whether genetic deficiency of macrophage COX-2 or mPGES-1 will improve cardiac remodeling after myocardial infarction. The downstream signal pathway and molecular mechanism will also be investigated. This study is fundamental in exploring new therapeutic strategies for acute myocardial infarction and will also pave the way for pursuing of macrophage COX-2 and mPGES-1 as novel drug targets that have the potential to alleviate inflammation and pain but also conserve cardiovascular efficacy.