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. 2021 Jan 15:323:243-250.
doi: 10.1016/j.ijcard.2020.08.042. Epub 2020 Aug 15.

The endocannabinoid 2-arachidonoylglycerol inhibits endothelial function and repair

Julian Jehle  1 , Lukas Eich  2 , Melina Danisch  2 , Sayeh Bagheri  2 , Elina Avraamidou  2 , Philipp Pfeifer  2 , Vedat Tiyerili  2 , Laura Bindila  3 , Beat Lutz  3 , Georg Nickenig  2
Affiliations

The endocannabinoid 2-arachidonoylglycerol inhibits endothelial function and repair

Julian Jehle et al. Int J Cardiol. .

Abstract

Background: Endothelial dysfunction promotes atherogenesis, vascular inflammation, and thrombus formation. Reendothelialization after angioplasty is required in order to prevent stent failure. Previous studies have highlighted the role of 2-arachidonoylglycerol (2-AG) in murine experimental atherogenesis and in human coronary artery disease. However, the impact of 2-AG on endothelial repair and leukocyte-endothelial cell adhesion is still unknown.

Methods: Endothelial repair was studied in two treatment groups of wildtype mice following electrical injury of the common carotid artery. One group received the monoacylglycerol lipase (MAGL)-inhibitor JZL184, which impairs 2-AG degradation and thus causes elevated 2-AG levels, the other group received DMSO (vehicle). The effect of 2-AG on human coronary artery endothelial cell (HCAEC) viability, leukocyte-endothelial cell adhesion, surface expression of adhesion molecules, and expression of endothelial NO synthase (NOS3) was studied in vitro.

Results: Elevated 2-AG levels significantly impaired reendothelialization in wildtype mice following electrical injury of the common carotid artery. In vitro, 2-AG significantly reduced viability of HCAEC. Additionally, 2-AG promoted adhesion of THP-1 monocytes to HCAEC following pre-treatment of the HCAEC with 2-AG. Adhesion molecules (E-selectin, ICAM-1 and VCAM-1) remained unchanged in arterial endothelial cells, whereas 2-AG suppressed the expression of NOS3 in HCAEC.

Conclusion and translational aspect: Elevated 2-AG levels hamper endothelial repair and HCAEC proliferation, while simultaneously facilitating leukocyte-endothelial cell adhesion. Given that 2-AG is elevated in patients with coronary artery disease and non-ST-segment elevation myocardial infarction, 2-AG might decrease reendothelialization after angioplasty and thus impact the clinical outcomes.

Keywords: 2-arachidonoylglycerol; Atherosclerosis; Endocannabinoid system; Endothelial repair; JZL184; Leukocyte–endothelial cell adhesion.

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