Myeloid Cell mPges-1 Deletion Attenuates Mortality Without Affecting Remodeling After Acute Myocardial Infarction in Mice
Myeloid Cell mPges-1 Deletion Attenuates Mortality Without Affecting Remodeling After Acute Myocardial Infarction in Mice
复制标题
骨髓细胞 mPges-1 缺失可降低小鼠急性心肌梗死后的死亡率而不影响重塑
DOI：
10.1124/jpet.118.256057
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发表时间：
2019-07-01
影响因子：
3.5
通讯作者：
FitzGerald, Garret A.
中科院分区：
文献类型：
--
作者：
Chen, Lihong;Yang, Guangrui;FitzGerald, Garret A.
选择性删除微粒体前列腺素E-2合成酶-1（mPges-1）在髓样细胞延缓动脉粥样硬化形成和抑制血管增生反应的损伤，而它不倾向于血栓形成或高血压。然而，使用来自辐射小鼠的骨髓移植的研究表明，髓样细胞mPGES-1促进实验性心肌梗死（MI）后的心脏重塑和存活。在这里，我们使用骨髓细胞中缺乏mPges-1的小鼠解决了这个问题，特别是巨噬细胞[Mac-mPges-1-敲除（KO）]，通过将mPges-1 floxed小鼠与LysMCre小鼠杂交并将它们进行冠状动脉结扎产生。心肌梗死后3、7和28天，通过形态学分析、超声心动图和有创血流动力学评估心脏结构和功能。尽管梗死面积相似，但与之前的报道相反，与野生型对照组相比，Mac-mPges-1-KO小鼠的MI后存活率显著提高。左心室收缩功能（通过射血分数、收缩末期容积缩短分数和+dP/dt反映）和舒张功能（通过舒张末期容积、-dP/dt和Tau反映）、心脏肥大（通过左心室尺寸反映）和纤维化染色在组间无差异。总之，我们发现髓系细胞中Cre-loxP介导的mPges-1缺失对MI后存活具有有利的影响，对MI后重塑没有可检测到的不利影响。这些结果进一步证明，靶向巨噬细胞mPGES-1可能是治疗和预防心血管炎性疾病的一种安全有效的方法。
Selective deletion of microsomal prostaglandin E-2 synthase-1 (mPges-1) in myeloid cells retards atherogenesis and suppresses the vascular proliferative response to injury, while it does not predispose to thrombogenesis or hypertension. However, studies using bone marrow transplants from irradiated mice suggest that myeloid cellmPGES-1 facilitates cardiac remodeling and prolongs survival after experimental myocardial infarction (MI). Here, we addressed this question using mice lacking mPges-1 in myeloid cells, particularly macrophages [Mac-mPges-1-knockout (KO)], generated by crossing mPges-1 floxed mice with LysMCre mice and subjecting them to coronary artery ligation. Cardiac structure and function were assessed by morphometric analysis, echocardiography, and invasive hemodynamics 3, 7, and 28 days after MI. Despite a similar infarct size, in contrast to the prior report, the post-MI survival rate was markedly improved in the Mac-mPges-1-KO mice compared with wild-type controls. Left ventricular systolic (reflected by ejection fraction, fractional shortness end systolic volume, and +dP/dt) and diastolic function (reflected by end diastolic volume, -dP/dt, and Tau), cardiac hypertrophy (reflected by left ventricular dimensions), and staining for fibrosis did not differ between the groups. In conclusion, we found that Cre-loxP-mediated deletion of mPges-1 in myeloid cells has favorable effects on post-MI survival, with no detectable adverse influence on post-MI remodeling. These results add to evidence that targeting macrophage mPGES-1 may represent a safe and efficacious approach to the treatment and prevention of cardiovascular inflammatory disease.