Endocannabinoid 2-arachidonoylglycerol is elevated in the coronary circulation during acute coronary syndrome

English version

Autoři: Julian Jehle ^aff001; Hanna Goerich ^aff001; Laura Bindila ^aff002; Beat Lutz ^aff002; Georg Nickenig ^aff001; Vedat Tiyerili ^aff001
Působiště autorů: Department of Internal Medicine II Cardiology, Pneumology, Angiology, University Hospital Bonn, Bonn, Germany ^aff001; Institute of Physiological Chemistry, University Medical Center of the Johannes Gutenberg University Mainz, Mainz, Germany ^aff002
Vyšlo v časopise: PLoS ONE 14(12)
Kategorie: Research Article
prolekare.web.journal.doi_sk: https://doi.org/10.1371/journal.pone.0227142

Souhrn

Objectives

The endocannabinoid system modulates coronary circulatory function and atherogenesis. The two major endocannabinoids (eCB), 2-arachidonoylglycerol (2-AG) and N-arachidonoylethanolamide (AEA), are increased in venous blood from patients with coronary artery disease (CAD). However, given their short half-life and their autocrine/paracrine mechanism of action, eCB levels in venous blood samples might not reflect arterial or coronary eCB concentrations. The aim of this cross-sectional study was to identify the local concentration profile of eCB and to detect whether and how this concentration profile changes in CAD and NSTEMI versus patients without CAD.

Methods and results

83 patients undergoing coronary angiography were included in this study. Patients were divided into three groups based on their definite diagnosis of a) no CAD, b) stable CAD, or c) non-ST-segment elevation myocardial infarction (NSTEMI). Blood was drawn from the arterial sheath and the aorta in all patients and additionally distal to the culprit coronary lesion in CAD- and NSTEMI patients. 2-AG levels varied significantly between patient groups and between the sites of blood extraction. The lowest levels were detected in patients without CAD; the highest 2-AG concentrations were detected in NSTEMI patients and in the coronary arteries. Peripheral 2-AG levels were significantly higher in NSTEMI patients (107.4 ± 28.4 pmol/ml) than in CAD- (17.4 ± 5.4 pmol/ml; p < 0.001), or no-CAD patients (23.9 ± 7.1 pmol/ml; p < 0.001). Moreover, coronary 2-AG levels were significantly higher in NSTEMI patients than in CAD patients (369.3 ± 57.2 pmol/ml vs. 240.1 ± 25.3 pmol/ml; p = 0.024).

Conclusions

2-AG showed significant variability in arterial blood samples drawn from distinct locations. Possibly, lesional macrophages synthesise 2-AG locally, which thereby contributes to endothelial dysfunction and local inflammation.

Klíčová slova:

Blood – Coronary heart disease – Coronary arteries – Aorta – Catheters – Myocardial infarction – Peas – Endocannabinoids

Zdroje

1. Libby P. Inflammation and cardiovascular disease mechanisms. Am J Clin Nutr. 2006;83: 456S–460S. doi: 10.1093/ajcn/83.2.456S 16470012

2. Devane W, Dysarz FA 3rd, Johnson MR, Melvin LS, Howlett AC. Determination and characterization of a cannabinoid receptor in rat brain. Mol Pharmacol. 1988;34: 605–613. 2848184

3. Devane WA, Hanus L, Breuer A, Pertwee RG, Stevenson LA, Griffin G, et al. Isolation and structure of a brain constituent that binds to the cannabinoid receptor. Science. 1992;258: 1946–1949. doi: 10.1126/science.1470919 1470919

4. Mechoulam R, Ben-Shabat S, Hanus L, Ligumsky M, Kaminski NE, Schatz AR, et al. Identification of an endogenous 2-monoglyceride, present in canine gut, that binds to cannabinoid receptors. Biochem Pharmacol. 1995;50: 83–90. doi: 10.1016/0006-2952(95)00109-d 7605349

5. Fowler CJ. Transport of endocannabinoids across the plasma membrane and within the cell. FEBS J. 2013;280: 1895–1904. doi: 10.1111/febs.12212 23441874

6. Quercioli A, Pataky Z, Vincenti G, Makoundou V, Di Marzo V, Montecucco F, et al. Elevated endocannabinoid plasma levels are associated with coronary circulatory dysfunction in obesity. Eur Heart J. 2011;32: 1369–1378. doi: 10.1093/eurheartj/ehr029 21303779

7. Quercioli A, Pataky Z, Montecucco F, Carballo S, Thomas A, Staub C, et al. Coronary vasomotor control in obesity and morbid obesity: contrasting flow responses with endocannabinoids, leptin, and inflammation. JACC Cardiovasc Imaging. 2012;5: 805–815. doi: 10.1016/j.jcmg.2012.01.020 22897994

8. Tamaki C, Nawa H, Takatori S, Oda S, Sendo T, Zamami Y, et al. Anandamide induces endothelium-dependent vasoconstriction and CGRPergic nerve-mediated vasodilatation in the rat mesenteric vascular bed. J Pharmacol Sci. 2012;118: 496–505. doi: 10.1254/jphs.11236fp 22510966

9. Wenzel D, Matthey M, Bindila L, Lerner R, Lutz B, Zimmer A, et al. Endocannabinoid anandamide mediates hypoxic pulmonary vasoconstriction. Proc Natl Acad Sci U S A. 2013;110: 18710–18715. doi: 10.1073/pnas.1308130110 24167249

10. Stanley CP, Hind WH, Tufarelli C, O’Sullivan SE. The endocannabinoid anandamide causes endothelium-dependent vasorelaxation in human mesenteric arteries. Pharmacol Res. 2016;113: 356–363. doi: 10.1016/j.phrs.2016.08.028 27633407

11. Lenglet S, Thomas A, Soehnlein O, Montecucco F, Burger F, Pelli G, et al. Fatty acid amide hydrolase deficiency enhances intraplaque neutrophil recruitment in atherosclerotic mice. Arterioscler Thromb Vasc Biol. 2013;33: 215–223. doi: 10.1161/ATVBAHA.112.300275 23241405

12. Hoyer FF, Khoury M, Slomka H, Kebschull M, Lerner R, Lutz B, et al. Inhibition of endocannabinoid-degrading enzyme fatty acid amide hydrolase increases atherosclerotic plaque vulnerability in mice. J Mol Cell Cardiol. 2014;66: 126–132. doi: 10.1016/j.yjmcc.2013.11.013 24286707

13. Jehle J, Hoyer FF, Schöne B, Pfeifer P, Schild K, Jenniches I, et al. Myeloid-Specific Deletion of Diacylglycerol Lipase α Inhibits Atherogenesis in ApoE-Deficient Mice. PLoS One. 2016;11: e0146267. doi: 10.1371/journal.pone.0146267 26731274

14. Jehle J, Schöne B, Bagheri S, Avraamidou E, Danisch M, Frank I, et al. Elevated levels of 2-arachidonoylglycerol promote atherogenesis in ApoE-/- mice. PLoS One. 2018;13: e0197751. doi: 10.1371/journal.pone.0197751 29813086

15. Randall MD. Endocannabinoids and the haematological system. Br J Pharmacol. 2007;152: 671–675. doi: 10.1038/sj.bjp.0707420 17704826

16. Howlett AC, Reggio PH, Childers SR, Hampson RE, Ulloa NM, Deutsch DG. Endocannabinoid tone versus constitutive activity of cannabinoid receptors. Br J Pharmacol. 2011;163: 1329–1343. doi: 10.1111/j.1476-5381.2011.01364.x 21545414

17. Sugamura K, Sugiyama S, Nozaki T, Matsuzawa Y, Izumiya Y, Miyata K, et al. Activated endocannabinoid system in coronary artery disease and antiinflammatory effects of cannabinoid 1 receptor blockade on macrophages. Circulation. 2009;119: 28–36. doi: 10.1161/CIRCULATIONAHA.108.811992 19103987

18. Maeda N, Osanai T, Kushibiki M, Fujiwara T, Tamura Y, Oowada S, et al. Increased serum anandamide level at ruptured plaque site in patients with acute myocardial infarction. Fundam Clin Pharmacol. 2009;23: 351–357. doi: 10.1111/j.1472-8206.2009.00679.x 19527302

19. Roffi M, Patrono C, Collet JP, Mueller C, Valgimigli M, Andreotti F et al.; ESC Scientific Document Group. 2015 ESC Guidelines for the management of acute coronary syndromes in patients presenting without persistent ST-segment elevation: Task Force for the Management of Acute Coronary Syndromes in Patients Presenting without Persistent ST-Segment Elevation of the European Society of Cardiology (ESC). Eur Heart J. 2016;37: 267–315. doi: 10.1093/eurheartj/ehv320 26320110

20. Montalescot G, Sechtem U, Achenbach S, Andreotti F, Arden C, Budaj A et al. 2013 ESC guidelines on the management of stable coronary artery disease: the Task Force on the management of stable coronary artery disease of the European Society of Cardiology. Eur Heart J. 2013;34: 2949–3003. doi: 10.1093/eurheartj/eht296 23996286

21. Lomazzo E, Bindila L, Remmers F, Lerner R, Schwitter C, Hoheisel U, et al. Therapeutic potential of inhibitors of endocannabinoid degradation for the treatment of stress-related hyperalgesia in an animal model of chronic pain. Neuropsychopharmacology. 2015;40: 488–501. doi: 10.1038/npp.2014.198 25100669

22. Berdyshev EV, Schimd PC, Krebsbach RJ, Schmid HHO. Activation of PAF receptors results in enhanced synthesis of 2-arachidonoylglycerol (2-AG) in immune cells. FASEB J. 2001;15: 2171–2178. doi: 10.1096/fj.01-0181com 11641243

23. Sido JM, Nagarkatti PS, Nagarkatti M. Production of endocannabinoids by activated T cells and B cells modulates inflammation associated with delayed-type hypersensitivity. Eur J Immunol. 2016;46: 1472–1479. doi: 10.1002/eji.201546181 27064137

24. Huang S, Frangogiannis NG. Anti-inflammatory therapies in myocardial infarction: failures, hopes and challenges. Br J Pharmacol. 2018;175: 1377–1400. doi: 10.1111/bph.14155 29394499

25. Brantl SA, Khandoga AL, Siess W. Mechanism of platelet activation induced by endocannabinoids in blood and plasma. Platelets. 2014;25: 151–161. doi: 10.3109/09537104.2013.803530 23789792

26. Fanola CL, Morrow DA, Cannon CP, Jarolim P, Lukas MA, Bode C, et al. Interleukin-6 and the Risk of Adverse Outcomes in Patients After an Acute Coronary Syndrome: Observations From the SOLID-TIMI 52 (Stabilization of Plaque Using Darapladib-Thrombolysis in Myocardial Infarction 52) Trial. J Am Heart Assoc. 2017;6: pii.e005637.

27. Ridker PM, Everett BM, Thuren T, MacFadyen JG, Chang WH, Ballantyne C, et al.; CANTOS Trial Group. Antiinflammatory Therapy with Canakinumab for Atherosclerotic Disease. N Engl J Med. 2017;377: 1119–1131. doi: 10.1056/NEJMoa1707914 28845751

28. Ridker PM, Everett BM, Pradhan A, MacFadyen JG, Solomon DH, Zaharris E, et al.; CIRT Investigators. Low-Dose Methotrexate for the Prevention of Atherosclerotic Events. N Engl J Med. 2018 [Epub ahead of print].