2-Arachidonoylglycerol mobilizes myeloid cells and worsens heart function after acute myocardial infarction
2-Arachidonoylglycerol mobilizes myeloid cells and worsens heart function after acute myocardial infarction
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DOI：
10.1093/cvr/cvy242
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发表时间：
2018-09
影响因子：
10.8
通讯作者：
Maximilian J. Schloss;M. Horckmans;R. Guillamat-Prats;D. Hering;Estelle Lauer;S. Lenglet;C. Weber;Aurélien Thomas;S. Steffens
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文献类型：
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作者：
Maximilian J. Schloss;M. Horckmans;R. Guillamat-Prats;D. Hering;Estelle Lauer;S. Lenglet;C. Weber;Aurélien Thomas;S. Steffens
目的 心肌梗塞（MI）导致缺血心肌内内源性大麻素的释放增加以及中性粒细胞和单核细胞的大量积累。这些骨髓细胞起源于骨髓中的造血前体细胞，并因心肌梗死而迅速动员起来。我们的目的是确定内源性大麻素信号传导是否参与缺血发作后的骨髓细胞动员和心脏募集。方法和结果 对野生型 (WT) C57BL6 小鼠静脉注射内源性大麻素 2-花生四烯酰甘油 (2-AG)，可诱导血液中性粒细胞和单核细胞计数快速增加（通过流式细胞术测量）。当使用大麻素受体 2 敲除小鼠时，这种效应被减弱。针对 WT 小鼠中诱导的 MI，脂质组学分析显示，梗死后 24 小时内源性大麻素 2-AG 的血浆和心脏水平显着升高，但 anandamide、棕榈酰乙醇酰胺和油酰乙醇酰胺没有变化。通过定量 RT-PCR 分析确定，这是梗死心脏中 2-AG 合成酶二酰甘油脂肪酶表达增加和代谢酶单酰甘油脂肪酶 (MAGL) 减少的结果。在骨髓中观察到相反的 mRNA 表达模式。与媒介物治疗的小鼠相比，用 JZL184 对 MAGL 进行药理学阻断，从而增加遭受 MI 的 WT 小鼠的全身 2-AG 水平，导致梗死后 24 小时心脏 CXCL1、CXCL2 和 MMP9 蛋白水平升高，以及心脏中性粒细胞和单核细胞计数更高。这些小鼠的心肌梗塞后炎症增加导致梗塞面积增加、组织学评估的心室疤痕形成受损以及超声心动图评估的心脏功能恶化，长达 21 天。同样，在心肌缺血再灌注模型中施用 JZL184 增加了心肌骨髓细胞的募集，并导致纤维化疤痕尺寸增大。结论 这些发现表明，由于组织水平改变而导致的内源性大麻素梯度变化有助于骨髓细胞从骨髓募集到梗塞心脏，对心脏愈合和功能产生至关重要的影响。
AIMS Myocardial infarction (MI) leads to an enhanced release of endocannabinoids and a massive accumulation of neutrophils and monocytes within the ischaemic myocardium. These myeloid cells originate from haematopoietic precursors in the bone marrow and are rapidly mobilized in response to MI. We aimed to determine whether endocannabinoid signalling is involved in myeloid cell mobilization and cardiac recruitment after ischaemia onset. METHODS AND RESULTS Intravenous administration of endocannabinoid 2-arachidonoylglycerol (2-AG) into wild type (WT) C57BL6 mice induced a rapid increase of blood neutrophil and monocyte counts as measured by flow cytometry. This effect was blunted when using cannabinoid receptor 2 knockout mice. In response to MI induced in WT mice, the lipidomic analysis revealed significantly elevated plasma and cardiac levels of the endocannabinoid 2-AG 24 h after infarction, but no changes in anandamide, palmitoylethanolamide, and oleoylethanolamide. This was a consequence of an increased expression of 2-AG synthesizing enzyme diacylglycerol lipase and a decrease of metabolizing enzyme monoacylglycerol lipase (MAGL) in infarcted hearts, as determined by quantitative RT-PCR analysis. The opposite mRNA expression pattern was observed in bone marrow. Pharmacological blockade of MAGL with JZL184 and thus increased systemic 2-AG levels in WT mice subjected to MI resulted in elevated cardiac CXCL1, CXCL2, and MMP9 protein levels as well as higher cardiac neutrophil and monocyte counts 24 h after infarction compared with vehicle-treated mice. Increased post-MI inflammation in these mice led to an increased infarct size, an impaired ventricular scar formation assessed by histology and a worsened cardiac function in echocardiography evaluations up to 21 days. Likewise, JZL184-administration in a myocardial ischaemia-reperfusion model increased cardiac myeloid cell recruitment and resulted in a larger fibrotic scar size. CONCLUSION These findings suggest that changes in endocannabinoid gradients due to altered tissue levels contribute to myeloid cell recruitment from the bone marrow to the infarcted heart, with crucial consequences on cardiac healing and function.