title: The endocannabinoid/endovanilloid N-arachidonoyl dopamine (NADA) and synthetic cannabinoid WIN55,212-2 abate the inflammatory activation of human endothelial cells.
abstract: Although cannabinoids, such as Δ(9)-tetrahydrocannabinol, have been studied extensively for their psychoactive effects, it has become apparent that certain cannabinoids possess immunomodulatory activity. Endothelial cells (ECs) are centrally involved in the pathogenesis of organ injury in acute inflammatory disorders, such as sepsis, because they express cytokines and chemokines, which facilitate the trafficking of leukocytes to organs, and they modulate vascular barrier function. In this study, we find that primary human ECs from multiple organs express the cannabinoid receptors CB1R, GPR18, and GPR55, as well as the ion channel transient receptor potential cation channel vanilloid type 1. In contrast to leukocytes, CB2R is only minimally expressed in some EC populations. Furthermore, we show that ECs express all of the known endocannabinoid (eCB) metabolic enzymes. Examining a panel of cannabinoids, we demonstrate that the synthetic cannabinoid WIN55,212-2 and the eCB N-arachidonoyl dopamine (NADA), but neither anandamide nor 2-arachidonoylglycerol, reduce EC inflammatory responses induced by bacterial lipopeptide, LPS, and TNFα. We find that endothelial CB1R/CB2R are necessary for the effects of NADA, but not those of WIN55,212-2. Furthermore, transient receptor potential cation channel vanilloid type 1 appears to counter the anti-inflammatory properties of WIN55,212-2 and NADA, but conversely, in the absence of these cannabinoids, its inhibition exacerbates the inflammatory response in ECs activated with LPS. These data indicate that the eCB system can modulate inflammatory activation of the endothelium and may have important implications for a variety of acute inflammatory disorders that are characterized by EC activation.
authors.affiliation: From the Department of Anesthesia and Perioperative Care.
authors.forename: Kevin
authors.initials: K
authors.lastname: Wilhelmsen
authors.forename: Samira
authors.initials: S
authors.lastname: Khakpour
authors.forename: Alphonso
authors.initials: A
authors.lastname: Tran
authors.forename: Kayla
authors.initials: K
authors.lastname: Sheehan
authors.forename: Mark
authors.initials: M
authors.lastname: Schumacher
authors.forename: Fengyun
authors.initials: F
authors.lastname: Xu
authors.forename: Judith
authors.initials: J
authors.lastname: Hellman
mesh_terms: D000700:Analgesics / Q000009:adverse effects* / Q000494:pharmacology; D001095:Arachidonic Acids / Q000009:adverse effects* / Q000494:pharmacology; D001426:Bacterial Proteins / Q000633:toxicity; D048588:Benzoxazines / Q000009:adverse effects* / Q000494:pharmacology; D002186:Cannabinoids / Q000009:adverse effects* / Q000494:pharmacology; D004298:Dopamine / Q000009:adverse effects / Q000031:analogs & derivatives* / Q000494:pharmacology; D061307:Human Umbilical Vein Endothelial Cells; D006801:Humans; D007249:Inflammation / Q000139:chemically induced / Q000378:metabolism / Q000473:pathology; D055666:Lipopeptides / Q000633:toxicity; D009025:Morpholines / Q000009:adverse effects* / Q000494:pharmacology; D009281:Naphthalenes / Q000009:adverse effects* / Q000494:pharmacology; D043882:Receptors, Cannabinoid / Q000378:metabolism; D050916:TRPV Cation Channels / Q000378:metabolism
chemical_list: D000700:Analgesics; D001095:Arachidonic Acids; D001426:Bacterial Proteins; D048588:Benzoxazines; D002186:Cannabinoids; D055666:Lipopeptides; D009025:Morpholines; D009281:Naphthalenes; D043882:Receptors, Cannabinoid; D050916:TRPV Cation Channels; C494484:TRPV1 receptor; C474941:arachidonyl dopamine; C070417:(3R)-((2,3-dihydro-5-methyl-3-((4-morpholinyl)methyl)pyrrolo-(1,2,3-de)-1,4-benzoxazin-6-yl)(1-naphthalenyl))methanone; D004298:Dopamine
keywords: Cannabinoid Receptors; Cannabinoids; Endocannabinoids; Endothelial Cell; Endothelial Dysfunction; Endothelium; Sepsis; TRP Channels; Toll-like Receptors (TLR)