The Role of CB1 and CB2 Cannabinoid Receptors in Myocardial Ischemia-Reperfusion Injury: Cardioprotective and Vasculoprotective Effects (a literature review)

Myocardial ischemia-reperfusion injury remains a major determinant of adverse post-infarction outcomes, contributing to irreversible myocardial damage, coronary microvascular dysfunction, an exaggerated inflammatory response, and pathological cardiac remodeling. In recent years, the endocannabinoid system has emerged as an important regulator of cellular adaptation to ischemia-reperfusion injury.

Aim: To summarize current experimental data on the role of CB1 and CB2 cannabinoid receptors in the mechanisms of cardioprotection and vasculoprotection in myocardial ischemia-reperfusion injury. The review assesses the localization and expression of cannabinoid receptors in the myocardium and vascular wall, their intracellular signaling pathways, and their functional significance in ischemia-reperfusion injury. Experimental studies on the effects of CB1 and CB2 receptor activation on infarct size, inflammatory response, endothelial function, coronary microvascular dysfunction, and post-infarction cardiac remodeling are discussed. Particular attention is also given to experimental data confirming the involvement of CB1 and CB2 receptors in the cardioprotective mechanisms of ischemic preconditioning, remote ischemic preconditioning, postconditioning, and heat stress. The available data indicate that the biological effects of cannabinoid receptors depend on receptor subtype, the mode of receptor activation, and the experimental model employed. In most experimental studies, activation of CB2 receptors has been associated with pronounced anti-inflammatory, vasculoprotective, and cardioprotective effects, whereas the role of CB1 receptors appears to be more complex and is influenced by the characteristics of the experimental model of myocardial ischemia-reperfusion injury, as well as the timing and pattern of receptor activation. Overall, current data suggest that cannabinoid receptors represent promising therapeutic targets for the development of novel pharmacological strategies aimed at preventing myocardial ischemia-reperfusion injury and adverse cardiac remodeling following myocardial infarction.

1. Panteleev O.O., Ryabov V.V. Cardiogenic shock: What's new? Siberian Journal of Clinical and Experimental Medicine. 2022;36(4):45–51. (In Russ). DOI: 10.29001/2073-8552-2021-36-4-45-51 EDN: TGEJXO

2. Ryabov V.V., Maslov L.N., Vyshlov E.V., et al. Ferroptosis, a Regulated Form of Cell Death, as a Target for the Development of Novel Drugs Preventing Ischemia/Reperfusion of Cardiac Injury, Cardiomyopathy and Stress-Induced Cardiac Injury. Int. J. Mol. Sci. 2024;25:897. DOI: 10.3390/ijms25020897 EDN: GUHALT

3. Zavadovsky K.V., Ryabov V.V., Vyshlov E.V., et al. Intra-myocardial hemorrhage and cardiac microvascular injury in ischemia/reperfusion. A systematic review of current evidences. Curr. Probl. Cardiol. 2025;50:102918. DOI: 10.1016/j.cpcardiol.2024.102918 EDN: DQONUY

4. Alekseeva Y.V., Vyshlov E.V., Pavlyukova E.N., et al. Impact of microvascular injury various types on function of left ventricular in patients with primary myocardial infarction with ST segment elevation. Kardiologiia. 2021;61:23–31. (In Russ). DOI: 10.18087/cardio.2021.5.n1500 EDN: ROQNIW

5. Maslov L.N., Khaliulin I., Zhang Y., et al. Prospects for Creation of Cardioprotective Drugs Based on Cannabinoid Receptor Agonists. J. Cardiovasc. Pharmacol. Ther. 2016;21:262–272. DOI: 10.1177/1074248415612593 EDN: WTAJCH

6. Matsuda L.A., Lolait S.J., Brownstein M.J., et al. Structure of a cannabinoid receptor and functional expression of the cloned cDNA. Nature. 1990;346:561–564. DOI: 10.1038/346561a0

7. Munro S., Thomas K.L., Abu-Shaar M. Molecular characterization of a peripheral receptor for cannabinoids. Nature. 1993;365:61–65. DOI: 10.1038/365061a0

8. Galiègue S., Mary S., Marchand J., et al. Expression of Central and Peripheral Cannabinoid Receptors in Human Immune Tissues and Leukocyte Subpopulations. Eur. J. Biochem. 1995;232:54–61. DOI: 10.1111/j.1432-1033.1995.tb20780.x

9. Devane W.A., Hanuš L., Breuer A., 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

10. Mechoulam R., Ben-Shabat S., Hanus L., 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

11. Shmist Y.A., Goncharov I., Eichler M., et al. Delta-9-tetrahydrocannabinol protects cardiac cells from hypoxia via CB2 receptor activation and nitric oxide production. Mol. Cell. Biochem. 2006;283:75-83. DOI: 10.1007/s11010-006-2346-y EDN: MCSICH

12. Qian L., Zhang S., Lin C., et al. Depression exacerbates myocardial ischemia-reperfusion injury in mice via CNR2 gene and MIF-AMPK signaling pathway. Int. J. Cardiol. 2024;416:132505. DOI: 10.1016/j.ijcard.2024.132505

13. Duerr G.D., Heinemann J.C., Kley J., et al. Myocardial maladaptation to pressure overload in CB2 receptor-deficient mice. J. Mol. Cell. Cardiol. 2019;133:86–98. DOI: 10.1016/j.yjmcc.2019.06.003

14. Möhnle P., Schütz S.V., Schmidt M., et al. MicroRNA-665 is involved in the regulation of the expression of the cardioprotective cannabinoid receptor CB2 in patients with severe heart failure. Biochem. Biophys. Res. Commun. 2014;451:516–521. DOI: 10.1016/j.bbrc.2014.08.008

15. Piotrowska Ż., Niezgoda M., Łebkowski W., et al. Sex differences in distribution of cannabinoid receptors (CB1 and CB2), S100A6 and CacyBP/SIP in human ageing hearts. Biol. Sex Differ. 2018;9:50. DOI: 10.1186/s13293-018-0209-3

16. Schloss M.J., Horckmans M., Guillamat-Prats R., et al. 2-Arachidonoylglycerol mobilizes myeloid cells and worsens heart function after acute myocardial infarction. Cardiovasc. Res. 2019;115:602–613. DOI: 10.1093/cvr/cvy242

17. Wagner J.A., Abesser M., Harvey-White J., Ertl G. 2-Arachidonylglycerol Acting on CB1 Cannabinoid Receptors Mediates Delayed Cardioprotection Induced by Nitric Oxide in Rat Isolated Hearts. J. Cardiovasc. Pharmacol. 2006;47:650–655. DOI: 10.1097/01.fjc.0000211752.08949.eb

18. Duerr G.D., Heinemann J.C., Dunkel S., et al. Myocardial hypertrophy is associated with inflammation and activation of endocannabinoid system in patients with aortic valve stenosis. Life Sci. 2013;92:976–983. DOI: 10.1016/j.lfs.2013.03.014

19. Wang P.-F., Jiang L.-S., Bu J., et al. Cannabinoid-2 Receptor Activation Protects Against Infarct and Ischemia-Reperfusion Heart Injury. J. Cardiovasc. Pharmacol. 2012;59:301–307. DOI: 10.1097/FJC.0b013e3182418997

20. Liu X., Zhang D., Dong X., et al. Pharmacological activation of CB2 receptor protects against ethanol-induced myocardial injury related to RIP1/RIP3/MLKL-mediated necroptosis. Mol. Cell. Biochem. 2020;474:1–14. DOI: 10.1007/s11010-020-03828-1

21. Sun H.-J., Lu Y., Wang H.-W., et al. Activation of Endocannabinoid Receptor 2 as a Mechanism of Propofol Pretreatment-Induced Cardioprotection against Ischemia-Reperfusion Injury in Rats. Oxid. Med. Cell. Longev. 2017;2017:2186383. DOI: 10.1155/2017/2186383

22. Sugiura T., Kodaka T., Nakane S., et al. Detection of an Endogenous Cannabimimetic Molecule, 2-Arachidonoylglycerol, and Cannabinoid CB1 Receptor mRNA in Human Vascular Cells: Is 2-Arachidonoylglycerol a Possible Vasomodulator? Biochem. Biophys. Res. Commun. 1998;243:838–843. DOI: 10.1006/bbrc.1998.8187

23. Lépicier P., Lagneux C., Sirois M.G., Lamontagne D. Endothelial CB1-receptors limit infarct size through NO formation in rat isolated hearts. Life Sci. 2007;81:1373–1380. DOI: 10.1016/j.lfs.2007.08.042

24. Stanley C.P., Hind W.H., Tufarelli C., O'Sullivan S.E. 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

25. Ugdyzhekova D.S., Krylatov A.V., Bernatskaya N.A., et al. Activation of Cannabinoid Receptors Decreases the Area of Ischemic Myocardial Necrosis. Bull. Exp. Biol. Med. 2002;133:125–126. DOI: 10.1023/A:1015526217332

26. Lépicier P., Bouchard J., Lagneux C., Lamontagne D. Endocannabinoids protect the rat isolated heart against ischaemia. Br. J. Pharmacol. 2003;139:805–815. DOI: 10.1038/sj.bjp.0705313

27. Underdown N.J., Hiley C.R., Ford W.R. Anandamide reduces infarct size in rat isolated hearts subjected to ischaemia-reperfusion by a novel cannabinoid mechanism. Br. J. Pharmacol. 2005;146:809–816. DOI: 10.1038/sj.bjp.0706391

28. Lasukova O.V., Maslov L.N., Ermakov S.Y., et al. Role of cannabinoid receptors in regulation of cardiac tolerance to ischemia and reperfusion. Biol. Bull. 2008;35:404–410. DOI: 10.1134/S1062359008040134

29. Di Filippo C., Rossi F., Rossi S., D'Amico M. Cannabinoid CB2 receptor activation reduces mouse myocardial ischemia-reperfusion injury: involvement of cytokine/chemokines and PMN. J. Leukoc. Biol. 2004;75:453–459. DOI: 10.1189/jlb.0703303

30. Montecucco F., Lenglet S., Braunersreuther V., et al. CB2 cannabinoid receptor activation is cardioprotective in a mouse model of ischemia/reperfusion. J. Mol. Cell. Cardiol. 2009;46:612–620. DOI: 10.1016/j.yjmcc.2008.12.014

31. Defer N., Wan J., Souktani R., et al. The cannabinoid receptor type 2 promotes cardiac myocyte and fibroblast survival and protects against ischemia/reperfusion-induced cardiomyopathy. FASEB J. 2009;23:2120–2130. DOI: 10.1096/fj.09-129478

32. Li Q., Shi M., Li B. Anandamide enhances expression of heat shock protein 72 to protect against ischemia-reperfusion injury in rat heart. J. Physiol. Sci. 2013;63:47–53. DOI: 10.1007/s12576-012-0228-5

33. Waldman M., Hochhauser E., Fishbein M. An ultra-low dose of tetrahydrocannabinol provides cardioprotection. Biochem. Pharmacol. 2013;85:1626–1633. DOI: 10.1016/j.bcp.2013.03.014

34. Li Q., Wang F., Zhang Y.-M., et al. Activation of Cannabinoid Type 2 Receptor by JWH133 Protects Heart Against Ischemia/Reperfusion-Induced Apoptosis. Cell. Physiol. Biochem. 2013;31:693–702. DOI: 10.1159/000350088

35. Li Q., Guo H., Maslov L.N., et al. Mitochondrial permeability transition pore plays a role in the cardioprotection of CB2 receptor against ischemia-reperfusion injury. Can. J. Physiol. Pharmacol. 2014;92:205–214. DOI: 10.1139/cjpp-2013-0293

36. Gorbunov A.S., Maslov L.N., Tsibulnikov S.Y., et al. CB-Receptor Agonist HU-210 Mimics the Postconditioning Phenomenon of Isolated Heart. Bull. Exp. Biol. Med. 2016;162:27-29. DOI: 10.1007/s10517-016-3536-6

37. Banaszkiewicz M., Tarwacka P., Krzywonos-Zawadzka A., et al. Δ9-Tetrahydrocannabinol (Δ9-THC) Improves Ischemia/Reperfusion Heart Dysfunction and Might Serve as a Cardioprotective Agent in the Future Treatment. Front. Biosci. (Landmark Ed). 2022;27(4):114. DOI: 10.31083/j.fbl2704114

38. Zhang M., Tian Q., Liu J. Cannabinoid Receptor-2 agonist AM1241 Attenuates Myocardial Ischemia-Reperfusion-Induced Oxidative Stress in Rats via Nrf2/HO-1 Pathway. Med. Princ. Pract. 2024;1–10. DOI: 10.1159/000540751

39. Wagner J.A., Hu K., Karcher J., et al. CB 1 cannabinoid receptor antagonism promotes remodeling and cannabinoid treatment prevents endothelial dysfunction and hypotension in rats with myocardial infarction. Br. J. Pharmacol. 2003;138:1251–1258. DOI: 10.1038/sj.bjp.0705156

40. Wang Y., Ma S., Wang Q., et al. Effects of cannabinoid receptor type 2 on endogenous myocardial regeneration by activating cardiac progenitor cells in mouse infarcted heart. Sci. China Life Sci. 2014;57:201–208. DOI: 10.1007/s11427-013-4604-z

41. Lu Y., Akinwumi B.C., Shao Z., Anderson H.D. Ligand Activation of Cannabinoid Receptors Attenuates Hypertrophy of Neonatal Rat Cardiomyocytes. J. Cardiovasc. Pharmacol. 2014;64:420–430. DOI: 10.1097/FJC.0000000000000134

42. Duerr G.D., Heinemann J.C., Gestrich C., et al. Impaired border zone formation and adverse remodeling after reperfused myocardial infarction in cannabinoid CB2 receptor deficient mice. Life Sci. 2015;138:8–17. DOI: 10.1016/j.lfs.2014.11.005

43. Li X., Han D., Tian Z., et al. Activation of Cannabinoid Receptor Type II by AM1241 Ameliorates Myocardial Fibrosis via Nrf2-Mediated Inhibition of TGF-β1/Smad3 Pathway in Myocardial Infarction Mice. Cell. Physiol. Biochem. 2016;39:1521–1536. DOI: 10.1159/000447855

44. Wagner J.A., Hu K., Bauersachs J., et al. Endogenous cannabinoids mediate hypotension after experimental myocardial infarction. J. Am. Coll. Cardiol. 2001;38:2048–2054. DOI: 10.1016/S0735-1097(01)01671-0

45. Rudź R., Schlicker E., Baranowska U., et al. Acute Myocardial Infarction Inhibits the Neurogenic Tachycardic and Vasopressor Response in Rats via Presynaptic Cannabinoid Type 1 Receptor. J. Pharmacol. Exp. Ther. 2012;343:198–205. DOI: 10.1124/jpet.112.196816

46. Andrag E., Curtis M.J. Feasibility of targeting ischaemia-related ventricular arrhythmias by mimicry of endogenous protection by endocannabinoids. Br. J. Pharmacol. 2013;169:1840–1848. DOI: 10.1111/bph.12252

47. Joyeux M. Endocannabinoids are implicated in the infarct size-reducing effect conferred by heat stress preconditioning in isolated rat hearts. Cardiovasc. Res. 2002;55:619–625. DOI: 10.1016/S0008-6363(02)00268-7

48. Hajrasouliha A.R., Tavakoli S., Ghasemi M., et al. Endogenous cannabinoids contribute to remote ischemic preconditioning via cannabinoid CB2 receptors in the rat heart. Eur. J. Pharmacol. 2008;579:246–252. DOI: 10.1016/j.ejphar.2007.09.034

49. Bouchard J.-F., Lépicier P., Lamontagne D. Contribution of endocannabinoids in the endothelial protection afforded by ischemic preconditioning in the isolated rat heart. Life Sci. 2003;72:1859–1870. DOI: 10.1016/S0024-3205(02)02474-8

50. González C., Herradón E., Abalo R., et al. Cannabinoid/agonist WIN 55,212-2 reduces cardiac ischaemia-reperfusion injury in Zucker diabetic fatty rats: role of CB2 receptors and iNOS/eNOS. Diabetes. Metab. Res. Rev. 2011;27:331–340. DOI: 10.1002/dmrr.1176