2-arachidonoylglycerol mobilizes myeloid cells and worsens heart function after acute myocardial infarction.

AIMS:

Myocardial infarction leads to an enhanced release of endocannabinoids and a massive accumulation of neutrophils and monocytes within the ischemic myocardium. These myeloid cells originate from hematopoietic precursors in the bone marrow and are rapidly mobilized in response to myocardial infarction. We aimed to determine whether endocannabinoid signaling is involved in myeloid cell mobilization and cardiac recruitment after ischemia onset.

METHODS AND RESULTS:

Intravenous administration of endocannabinoid 2-arachidonoylglycerol into wildtype 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 myocardial infarction induced in wildtype mice, the lipidomic analysis revealed significantly elevated plasma and cardiac levels of the endocannabinoid 2-arachidonoylglycerol 24 h after infarction, but no changes in anandamide, palmitoylethanolamide and oleoylethanolamide. This was a consequence of an increased expression of 2-arachidonoylglycerol synthesizing enzyme diacylglycerol lipase and a decrease of metabolizing enzyme monoacylglycerol lipase in infarcted hearts, as determined by quantitative RT-PCR analysis. The opposite mRNA expression pattern was observed in bone marrow. Pharmacological blockade of monoacylglycerol lipase with JZL184 and thus increased systemic 2-arachidonoylglycerol levels in wildtype mice subjected to myocardial infarction resulted in elevated cardiac CXCL1, CXCL2 and MMP9 protein levels as well as higher cardiac neutrophil and monocyte counts 24 h after infarction compared to vehicle-treated mice. Increased post-myocardial infarction 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 ischemia-reperfusion model increased cardiac myeloid cell recruitment and resulted in a larger fibrotic scar size.

CONCLUSIONS:

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.