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

Abstract

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.

Chronic Cannabidiol Administration Fails to Diminish Blood Pressure in Rats with Primary and Secondary Hypertension Despite Its Effects on Cardiac and Plasma Endocannabinoid System, Oxidative Stress and Lipid Metabolism

“…Its levels in WKY and SHAM were 220 and 75 times higher than the concentration of the best-known endocannabinoid AEA, respectively. This is an important observation in the light of recent publications that 2-AG in vivo worsens heart function after acute myocardial infarction [47], increases the severity of the cerebral blood flow deficit [55] or promotes atherogenesis [56] on the one hand but ameliorates inflammatory stress-induced insulin resistance in cardiomyocytes on the other [57]. Unfortunately, there are only limited data regarding the cardiovascular effects of endocannabinoids other than 2-AG and AEA.…”

“…Surprisingly, the decreases in ECBs were observed in spite of the reduced FAAH activity. Due to the vasodilatory and/or hypotensive effects of AEA and OEA [64,65], the CBD-induced decrease in AEA and OEA levels appears to be unfavourable in hypertension whereas the decrease in cardiac 2-AG concentration might be beneficial because worsening of cardiac function by 2-AG has been described recently [47].…”

“…CBD inhibits fatty acid amide hydrolase (FAAH) [43] and can interact with the anandamide membrane transporter [44,45] both of which may increase levels of endocannabinoids and related lipids. They may have positive effects and be used as a target in pharmacotherapy [46] but in some cases, can also exert untoward actions [47]. In this context, one should keep in mind that the FAAH inhibitor URB597 and hypertension may affect cardiac and plasma oxidative stress, endocannabinoid levels and lipid metabolism in a model-dependent manner [48,49].…”

A Guide to Targeting the Endocannabinoid System in Drug Design

“…The data on cardioprotective impact of endocannabinoids are conflicting and are based mainly on studies on rodents. Some studies suggest 2-AG deleterious impact in myocardial infraction (MI) via CB2 activation and myeloid cells recruitment, as shown by the MAGL inhibitor, JZL184 (16 mg/kg) in mice [261]. According to another study on rodents, the CB2 activation promotes myocardial adaptation to pressure overload and remodeling via apoptosis prevention, inflammation and oxidative stress reduction, and regulation of contractile elements' expression in cardiomyocytes [262].…”

Proteomic Analysis of Myocardia Containing the Obscurin R4344Q Mutation Linked to Hypertrophic Cardiomyopathy

“…In addition to the proteins discussed above, others involved in molecular transport have been shown to confer cardiac protection or exacerbate cardiac pathology. Among those, cardiac-specific overexpression of signal-regulatory protein alpha (Sirpα) has been suggested to attenuate pressure overloadinduced cardiac hypertrophy in mice (Jiang et al, 2014), whereas mice treated with a pharmacological inhibitor of monoglyceride lipase (Mgll) exhibit increased infarct size and worsened cardiac function post-myocardial infarction (Schloss et al, 2019). Interestingly, while Sirpα is up-regulated by 17.8%, Mgll is down-regulated by 14.6% in the R4344Q myocardium (Table 4).…”