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

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.

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。

心肌梗死是心血管疾病致死致残的主要原因。心室重构是指心肌梗死等各种损伤后由于心肌细胞及细胞间质形态结构的改变，使心脏结构功能按照一定的模式进行重塑的过程。深入探讨心肌梗死和心室重构发生的分子机制，有助于为早期防治心肌梗死供新的途径，也是延缓慢性心力衰竭发生发展的关键所在。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作用备受关注。本项目首先通过对PGE2信号通路，尤其是其终末合成酶mPGES-1，在左冠状动脉前降支结扎诱导的小鼠心肌梗死和心室重构中的作用和机制进行探讨，发现：1，心肌梗死可以显著诱导COX-2/mPGES-1/PGE2/EP信号通路的激活。2，不论是全身性还是巨噬细胞特异性mPGES-1基因敲除均不影响小鼠心肌梗死后的心室重构过程，不加剧心功能紊乱，且选择性敲除巨噬细胞mPGES-1还可以显著提高小鼠心肌梗死后的存活率。此外，为了进一步探讨mPGES-1在心室重构中的作用，我们利用异丙肾上腺素和链脲佐菌素注射分别诱导了另两种心室重构的小鼠模型。研究发现，敲除mPGES-1基因可以显著减轻异丙肾上腺素诱导的心脏纤维化。阻断COX-2或mPGES-1则可能通过抑制高糖诱导的心肌细胞自噬进而拮抗糖尿病诱导的心肌肥厚和心脏纤维化。本项目的研究结果，不仅为PGE2信号通路在心肌梗死和心室重构中的作用提供新观点，也为以mPGES-1，尤其是巨噬细胞mPGES-1，为新靶点的具有心血管保护作用的解热镇痛抗炎药的研发提供了重要的理论依据。