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The endocannabinoid system in cardiovascular function: novel insights and clinical implications

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Abstract

Rationale

Cardiovascular disease is now recognized as the number one cause of death in the world, and the size of the population at risk continues to increase rapidly. The dysregulation of the endocannabinoid (eCB) system plays a central role in a wide variety of conditions including cardiovascular disorders. Cannabinoid receptors, their endogenous ligands, as well as enzymes conferring their synthesis and degradation, exhibit overlapping distributions in the cardiovascular system. Furthermore, the pharmacological manipulation of the eCB system has effects on blood pressure, cardiac contractility, and endothelial vasomotor control. Growing evidence from animal studies supports the significance of the eCB system in cardiovascular disorders.

Objective

To summarize the literature surrounding the eCB system in cardiovascular function and disease and the new compounds that may potentially extend the range of available interventions.

Results

Drugs targeting CB1R, CB2R, TRPV1 and PPARs are proven effective in animal models mimicking cardiovascular disorders such as hypertension, atherosclerosis and myocardial infarction. Despite the setback of two clinical trials that exhibited unexpected harmful side-effects, preclinical studies are accelerating the development of more selective drugs with promising results devoid of adverse effects.

Conclusion

Over the last years, increasing evidence from basic and clinical research supports the role of the eCB system in cardiovascular function. Whereas new discoveries are paving the way for the identification of novel drugs and therapeutic targets, the close cooperation of researchers, clinicians and pharmaceutical companies is needed to achieve successful outcomes.

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References

  1. Zias J, Stark H, Sellgman J et al (1993) Early medical use of cannabis. Nature 363:215. https://doi.org/10.1038/363215a0

    CAS  PubMed  Google Scholar 

  2. Noyes R, Brunk SF, Baram DA, Canter A (1975) Analgesic effect of delta-9-tetrahydrocannabinol. J Clin Pharmacol 15:139–143

    Article  PubMed  Google Scholar 

  3. Frankel JP, Hughes A, Lees AJ, Stern GM (1990) Marijuana for parkinsonian tremor. J Neurol Neurosurg Psychiatr 53:436

    Article  CAS  Google Scholar 

  4. Beal JE, Olson R, Lefkowitz L et al (1997) Long-term efficacy and safety of dronabinol for acquired immunodeficiency syndrome-associated anorexia. J Pain Symptom Manage 14:7–14. https://doi.org/10.1016/S0885-3924(97)00038-9

    Article  CAS  PubMed  Google Scholar 

  5. Weiss JL, Watanabe AM, Lemberger L et al (1972) Cardiovascular effects of delta-9-tetrahydrocannabinol in man. Clin Pharmacol Ther 13:671–684

    Article  CAS  PubMed  Google Scholar 

  6. Hillard CJ (2000) Endocannabinoids and vascular function. J Pharmacol Exp Ther 294:27–32

    CAS  PubMed  Google Scholar 

  7. Lake KD, Compton DR, Varga K et al (1997) Cannabinoid-induced hypotension and bradycardia in rats mediated by CB1-like cannabinoid receptors. J Pharmacol Exp Ther 281:1030–1037

    CAS  PubMed  Google Scholar 

  8. Lake KD, Martin BR, Kunos G, Varga K (1997) Cardiovascular effects of anandamide in anesthetized and conscious normotensive and hypertensive rats. Hypertension 29:1204–1210

    Article  CAS  PubMed  Google Scholar 

  9. Randall MD, Kendall DA (1997) Involvement of a cannabinoid in endothelium-derived hyperpolarizing factor-mediated coronary vasorelaxation. Eur J Pharmacol 335:205–209

    Article  CAS  PubMed  Google Scholar 

  10. Hiley CR, Ford WR (2003) Endocannabinoids as mediators in the heart: a potential target for therapy of remodelling after myocardial infarction? Br J Pharmacol 138:1183–1184. https://doi.org/10.1038/sj.bjp.0705155

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  11. Duerr GD, Heinemann JC, Gestrich C et al (2015) Impaired border zone formation and adverse remodeling after reperfused myocardial infarction in cannabinoid CB2 receptor deficient mice. Life Sci 138:8–17. https://doi.org/10.1016/j.lfs.2014.11.005

    Article  CAS  PubMed  Google Scholar 

  12. Matsuda LA, Lolait SJ, Brownstein MJ et al (1990) Structure of a cannabinoid receptor and functional expression of the cloned cDNA. Nature 346:561–564. https://doi.org/10.1038/346561a0

    Article  CAS  PubMed  Google Scholar 

  13. Munro S, Thomas KL, Abu-Shaar M (1993) Molecular characterization of a peripheral receptor for cannabinoids. Nature 365:61–65. https://doi.org/10.1038/365061a0

    Article  CAS  PubMed  Google Scholar 

  14. Randhawa PK, Jaggi AS (2017) TRPV1 channels in cardiovascular system: a double edged sword? Int J Cardiol 228:103–113. https://doi.org/10.1016/j.ijcard.2016.11.205

    Article  PubMed  Google Scholar 

  15. O’Sullivan SE, Tarling EJ, Bennett AJ et al (2005) Novel time-dependent vascular actions of Delta9-tetrahydrocannabinol mediated by peroxisome proliferator-activated receptor gamma. Biochem Biophys Res Commun 337:824–831. https://doi.org/10.1016/j.bbrc.2005.09.121

    Article  PubMed  CAS  Google Scholar 

  16. Penumarti A, Abdel-Rahman AA (2014) The novel endocannabinoid receptor GPR18 is expressed in the rostral ventrolateral medulla and exerts tonic restraining influence on blood pressure. J Pharmacol Exp Ther 349:29–38. https://doi.org/10.1124/jpet.113.209213

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  17. AlSuleimani YM, Hiley CR (2015) The GPR55 agonist lysophosphatidylinositol relaxes rat mesenteric resistance artery and induces Ca(2 +) release in rat mesenteric artery endothelial cells. Br J Pharmacol 172:3043–3057. https://doi.org/10.1111/bph.13107

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  18. Overton HA, Babbs AJ, Doel SM et al (2006) Deorphanization of a G protein-coupled receptor for oleoylethanolamide and its use in the discovery of small-molecule hypophagic agents. Cell Metab 3:167–175. https://doi.org/10.1016/j.cmet.2006.02.004

    Article  CAS  PubMed  Google Scholar 

  19. Mechoulam R, Fride E, Di Marzo V (1998) Endocannabinoids. Eur J Pharmacol 359:1–18

    Article  CAS  PubMed  Google Scholar 

  20. Liu J, Gao B, Mirshahi F et al (2000) Functional CB1 cannabinoid receptors in human vascular endothelial cells. Biochem J 346(Pt 3):835–840

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  21. Bonz A, Laser M, Küllmer S et al (2003) Cannabinoids acting on CB1 receptors decrease contractile performance in human atrial muscle. J Cardiovasc Pharmacol 41:657–664

    Article  CAS  PubMed  Google Scholar 

  22. Mailleux P, Vanderhaeghen JJ (1992) Distribution of neuronal cannabinoid receptor in the adult rat brain: a comparative receptor binding radioautography and in situ hybridization histochemistry. Neuroscience 48:655–668

    Article  CAS  PubMed  Google Scholar 

  23. Wang T, Li G-Q, Zhang H-P et al (2017) Overactivation of cannabinoid receptor type 1 in rostral ventrolateral medulla promotes cardiovascular responses in spontaneously hypertensive rats. J Hypertens 35:538–545. https://doi.org/10.1097/HJH.0000000000001179

    Article  CAS  PubMed  Google Scholar 

  24. Grzęda E, Schlicker E, Toczek M et al (2017) CB1 receptor activation in the rat paraventricular nucleus induces bi-directional cardiovascular effects via modification of glutamatergic and GABAergic neurotransmission. Naunyn Schmiedebergs Arch Pharmacol 390:25–35. https://doi.org/10.1007/s00210-016-1302-y

    Article  PubMed  CAS  Google Scholar 

  25. Toczek M, Schlicker E, Grzęda E, Malinowska B (2015) Enhanced function of inhibitory presynaptic cannabinoid CB1 receptors on sympathetic nerves of DOCA-salt hypertensive rats. Life Sci 138:78–85. https://doi.org/10.1016/j.lfs.2015.03.022

    Article  CAS  PubMed  Google Scholar 

  26. Rajesh M, Mukhopadhyay P, Haskó G, Pacher P (2008) Cannabinoid CB1 receptor inhibition decreases vascular smooth muscle migration and proliferation. Biochem Biophys Res Commun 377:1248–1252. https://doi.org/10.1016/j.bbrc.2008.10.159

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  27. Dol-Gleizes F, Paumelle R, Visentin V et al (2009) Rimonabant, a selective cannabinoid CB1 receptor antagonist, inhibits atherosclerosis in LDL receptor-deficient mice. Arterioscler Thromb Vasc Biol 29:12–18. https://doi.org/10.1161/ATVBAHA.108.168757

    Article  CAS  PubMed  Google Scholar 

  28. Bonhaus DW, Chang LK, Kwan J, Martin GR (1998) Dual activation and inhibition of adenylyl cyclase by cannabinoid receptor agonists: evidence for agonist-specific trafficking of intracellular responses. J Pharmacol Exp Ther 287:884–888

    CAS  PubMed  Google Scholar 

  29. Lozovaya N, Min R, Tsintsadze V, Burnashev N (2009) Dual modulation of CNS voltage-gated calcium channels by cannabinoids: focus on CB1 receptor-independent effects. Cell Calcium 46:154–162. https://doi.org/10.1016/j.ceca.2009.07.007

    Article  CAS  PubMed  Google Scholar 

  30. Maneuf YP, Brotchie JM (1997) Paradoxical action of the cannabinoid WIN 55,212-2 in stimulated and basal cyclic AMP accumulation in rat globus pallidus slices. Br J Pharmacol 120:1397–1398. https://doi.org/10.1038/sj.bjp.0701101

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  31. Gebremedhin D, Lange AR, Campbell WB et al (1999) Cannabinoid CB1 receptor of cat cerebral arterial muscle functions to inhibit L-type Ca2+ channel current. Am J Physiol 276:H2085–H2093

    CAS  PubMed  Google Scholar 

  32. Kano M, Ohno-Shosaku T, Hashimotodani Y et al (2009) Endocannabinoid-mediated control of synaptic transmission. Physiol Rev 89:309–380. https://doi.org/10.1152/physrev.00019.2008

    Article  CAS  PubMed  Google Scholar 

  33. Bénard GG, Massa FF, Puente NN et al (2012) Mitochondrial CB1 receptors regulate neuronal energy metabolism. Nat Neurosci 15:558–564. https://doi.org/10.1038/nn.3053

    Article  PubMed  CAS  Google Scholar 

  34. Ledent C, Valverde O, Cossu G et al (1999) Unresponsiveness to cannabinoids and reduced addictive effects of opiates in CB1 receptor knockout mice. Science 283:401–404

    Article  CAS  PubMed  Google Scholar 

  35. Vollmer RR, Cavero I, Ertel RJ et al (1974) Role of the central autonomic nervous system in the hypotension and bradycardia induced by (-)-delta 9-trans-tetrahydrocannabinol. J Pharm Pharmacol 26:186–192

    Article  CAS  PubMed  Google Scholar 

  36. Niederhoffer N, Szabo B (2000) Cannabinoids cause central sympathoexcitation and bradycardia in rabbits. J Pharmacol Exp Ther 294:707–713

    CAS  PubMed  Google Scholar 

  37. Ishac EJ, Jiang L, Lake KD et al (1996) Inhibition of exocytotic noradrenaline release by presynaptic cannabinoid CB1 receptors on peripheral sympathetic nerves. Br J Pharmacol 118:2023–2028. https://doi.org/10.1111/(ISSN)1476-5381

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  38. Vidrio H, Sánchez-Salvatori MA, Medina M (1996) Cardiovascular effects of (-)-11-OH-delta 8-tetrahydrocannabinol-dimethylheptyl in rats. J Cardiovasc Pharmacol 28:332–336

    Article  CAS  PubMed  Google Scholar 

  39. Szabo B, Nordheim U, Niederhoffer N (2001) Effects of cannabinoids on sympathetic and parasympathetic neuroeffector transmission in the rabbit heart. J Pharmacol Exp Ther 297:819–826

    CAS  PubMed  Google Scholar 

  40. Huestis MA, Gorelick DA, Heishman SJ et al (2001) Blockade of effects of smoked marijuana by the CB1-selective cannabinoid receptor antagonist SR141716. Arch Gen Psychiatr 58:322–328

    Article  CAS  PubMed  Google Scholar 

  41. Cabral GA, Raborn ES, Griffin L et al (2008) CB2 receptors in the brain: role in central immune function. Br J Pharmacol 153:240–251. https://doi.org/10.1038/sj.bjp.0707584

    Article  CAS  PubMed  Google Scholar 

  42. Galiegue S, Mary S, Marchand J et al (1995) Expression of central and peripheral cannabinoid receptors in human immune tissues and leukocyte subpopulations. Eur J Biochem 232:54–61

    Article  CAS  PubMed  Google Scholar 

  43. Pacher P, Mechoulam R (2011) Is lipid signaling through cannabinoid 2 receptors part of a protective system? Prog Lipid Res 50:193–211. https://doi.org/10.1016/j.plipres.2011.01.001

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  44. Ramirez SH, Haskó J, Skuba A et al (2012) Activation of cannabinoid receptor 2 attenuates leukocyte-endothelial cell interactions and blood-brain barrier dysfunction under inflammatory conditions. J Neurosci 32:4004–4016. https://doi.org/10.1523/JNEUROSCI.4628-11.2012

    Article  CAS  PubMed  PubMed Central  Google Scholar 

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

    Article  CAS  PubMed  Google Scholar 

  46. Rajesh M, Mukhopadhyay P, Hasko G et al (2008) CB2 cannabinoid receptor agonists attenuate TNF-alpha-induced human vascular smooth muscle cell proliferation and migration. Br J Pharmacol 153:347–357. https://doi.org/10.1038/sj.bjp.0707569

    Article  CAS  PubMed  Google Scholar 

  47. Bouaboula MM, Poinot-Chazel CC, Bourrié BB et al (1995) Activation of mitogen-activated protein kinases by stimulation of the central cannabinoid receptor CB1. Biochem J 312(Pt 2):637–641

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  48. Demuth DG, Molleman A (2006) Cannabinoid signalling. Life Sci 78:549–563. https://doi.org/10.1016/j.lfs.2005.05.055

    Article  CAS  PubMed  Google Scholar 

  49. Zoratti C, Kipmen-Korgun D, Osibow K et al (2003) Anandamide initiates Ca(2+) signaling via CB2 receptor linked to phospholipase C in calf pulmonary endothelial cells. Br J Pharmacol 140:1351–1362. https://doi.org/10.1038/sj.bjp.0705529

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  50. Steffens S, Pacher P (2012) Targeting cannabinoid receptor CB(2) in cardiovascular disorders: promises and controversies. Br J Pharmacol 167:313–323. https://doi.org/10.1111/j.1476-5381.2012.02042.x

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  51. Kohno M, Hasegawa H, Inoue A et al (2006) Identification of N-arachidonylglycine as the endogenous ligand for orphan G-protein-coupled receptor GPR18. Biochem Biophys Res Commun 347:827–832. https://doi.org/10.1016/j.bbrc.2006.06.175

    Article  CAS  PubMed  Google Scholar 

  52. Járai Z, Wagner JA, Varga K et al (1999) Cannabinoid-induced mesenteric vasodilation through an endothelial site distinct from CB1 or CB2 receptors. Proc Natl Acad Sci USA 96:14136–14141

    Article  PubMed  PubMed Central  Google Scholar 

  53. MacIntyre J, Dong A, Straiker A et al (2014) Cannabinoid and lipid-mediated vasorelaxation in retinal microvasculature. Eur J Pharmacol 735:105–114. https://doi.org/10.1016/j.ejphar.2014.03.055

    Article  CAS  PubMed  Google Scholar 

  54. Vassilatis DK, Hohmann JG, Zeng H et al (2003) The G protein-coupled receptor repertoires of human and mouse. Proc Natl Acad Sci USA 100:4903–4908. https://doi.org/10.1073/pnas.0230374100

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  55. Offertáler L, Mo FM, Bátkai S et al (2003) Selective ligands and cellular effectors of a G protein-coupled endothelial cannabinoid receptor. Mol Pharmacol 63:699–705

    Article  PubMed  Google Scholar 

  56. Mo FM, Offertáler L, Kunos G (2004) Atypical cannabinoid stimulates endothelial cell migration via a Gi/Go-coupled receptor distinct from CB1, CB2 or EDG-1. Eur J Pharmacol 489:21–27. https://doi.org/10.1016/j.ejphar.2004.02.034

    Article  CAS  PubMed  Google Scholar 

  57. Zhang MJ, Sansbury BE, Hellmann J et al (2016) Resolvin D2 enhances postischemic revascularization while resolving inflammation. Circulation 134:666–680. https://doi.org/10.1161/CIRCULATIONAHA.116.021894

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  58. Caterina MJ, Schumacher MA, Tominaga M et al (1997) The capsaicin receptor: a heat-activated ion channel in the pain pathway. Nature 389:816–824. https://doi.org/10.1038/39807

    Article  CAS  PubMed  Google Scholar 

  59. Zahner MR, Li D-P, Chen S-R, Pan H-L (2003) Cardiac vanilloid receptor 1-expressing afferent nerves and their role in the cardiogenic sympathetic reflex in rats. J Physiol 551:515–523. https://doi.org/10.1113/jphysiol.2003.048207

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  60. Gao F, Liang Y, Wang X et al (2014) TRPV1 activation attenuates high-salt diet-induced cardiac hypertrophy and fibrosis through PPAR-δ upregulation. PPAR Res 2014:1–12. https://doi.org/10.1155/2014/491963

    Article  CAS  Google Scholar 

  61. Yang D, Luo Z, Ma S et al (2010) Activation of TRPV1 by dietary capsaicin improves endothelium-dependent vasorelaxation and prevents hypertension. Cell Metab 12:130–141. https://doi.org/10.1016/j.cmet.2010.05.015

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  62. Li B-H, Yin Y-W, Liu Y et al (2014) TRPV1 activation impedes foam cell formation by inducing autophagy in oxLDL-treated vascular smooth muscle cells. Cell Death Dis 5:e1182. https://doi.org/10.1038/cddis.2014.146

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  63. Harper AGS, Brownlow SL, Sage SO (2009) A role for TRPV1 in agonist-evoked activation of human platelets. J Thromb Haemost 7:330–338. https://doi.org/10.1111/j.1538-7836.2008.03231.x

    Article  CAS  PubMed  Google Scholar 

  64. Zygmunt PM, Petersson J, Andersson DA et al (1999) Vanilloid receptors on sensory nerves mediate the vasodilator action of anandamide. Nature 400:452–457. https://doi.org/10.1038/22761

    Article  CAS  PubMed  Google Scholar 

  65. Poblete IM, Orliac ML, Briones R et al (2005) Anandamide elicits an acute release of nitric oxide through endothelial TRPV1 receptor activation in the rat arterial mesenteric bed. J Physiol 568:539–551. https://doi.org/10.1113/jphysiol.2005.094292

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  66. De Petrocellis L, Vellani V, Schiano-Moriello A et al (2008) Plant-derived cannabinoids modulate the activity of transient receptor potential channels of ankyrin type-1 and melastatin type-8. J Pharmacol Exp Ther 325:1007–1015. https://doi.org/10.1124/jpet.107.134809

    Article  PubMed  CAS  Google Scholar 

  67. Pertwee RG, Howlett AC, Abood ME et al (2010) International union of basic and clinical pharmacology. LXXIX. Cannabinoid receptors and their ligands: beyond CB1 and CB2. Pharmacol Rev 62:588–631. https://doi.org/10.1124/pr.110.003004

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  68. Pertwee RG (2006) The pharmacology of cannabinoid receptors and their ligands: an overview. Int J Obes (Lond) 30(Suppl 1):S13–S18. https://doi.org/10.1038/sj.ijo.0803272

    Article  CAS  Google Scholar 

  69. Marshall NJ, Liang L, Bodkin J et al (2013) A role for TRPV1 in influencing the onset of cardiovascular disease in obesity. Hypertension 61:246–252. https://doi.org/10.1161/HYPERTENSIONAHA.112.201434

    Article  CAS  PubMed  Google Scholar 

  70. Lang H, Li Q, Yu H et al (2015) Activation of TRPV1 attenuates high salt-induced cardiac hypertrophy through improvement of mitochondrial function. Br J Pharmacol 172:5548–5558. https://doi.org/10.1111/bph.12987

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  71. Buckley CL, Stokes AJ (2011) Mice lacking functional TRPV1 are protected from pressure overload cardiac hypertrophy. Channels (Austin) 5:367–374. https://doi.org/10.4161/chan.5.4.17083

    Article  CAS  PubMed Central  Google Scholar 

  72. Issemann I, Green S (1990) Activation of a member of the steroid hormone receptor superfamily by peroxisome proliferators. Nature 347:645–650. https://doi.org/10.1038/347645a0

    Article  CAS  PubMed  Google Scholar 

  73. Braissant O, Foufelle F, Scotto C et al (1996) Differential expression of peroxisome proliferator-activated receptors (PPARs): tissue distribution of PPAR-alpha, -beta, and -gamma in the adult rat. Endocrinology 137:354–366. https://doi.org/10.1210/endo.137.1.8536636

    Article  CAS  PubMed  Google Scholar 

  74. Belanger AJ, Lu H, Date T et al (2002) Hypoxia up-regulates expression of peroxisome proliferator-activated receptor gamma angiopoietin-related gene (PGAR) in cardiomyocytes: role of hypoxia inducible factor 1alpha. J Mol Cell Cardiol 34:765–774

    Article  CAS  PubMed  Google Scholar 

  75. Wayman NS, Hattori Y, McDonald MC et al (2002) Ligands of the peroxisome proliferator-activated receptors (PPAR-gamma and PPAR-alpha) reduce myocardial infarct size. FASEB J 16:1027–1040. https://doi.org/10.1096/fj.01-0793com

    Article  CAS  PubMed  Google Scholar 

  76. Inoue I, Shino K, Noji S et al (1998) Expression of peroxisome proliferator-activated receptor alpha (PPAR alpha) in primary cultures of human vascular endothelial cells. Biochem Biophys Res Commun 246:370–374. https://doi.org/10.1006/bbrc.1998.8622

    Article  CAS  PubMed  Google Scholar 

  77. Marx N, Bourcier T, Sukhova GK et al (1999) PPARgamma activation in human endothelial cells increases plasminogen activator inhibitor type-1 expression: PPARgamma as a potential mediator in vascular disease. Arterioscler Thromb Vasc Biol 19:546–551

    Article  CAS  PubMed  Google Scholar 

  78. Piqueras L, Reynolds AR, Hodivala-Dilke KM et al (2007) Activation of PPARbeta/delta induces endothelial cell proliferation and angiogenesis. Arterioscler Thromb Vasc Biol 27:63–69. https://doi.org/10.1161/01.ATV.0000250972.83623.61

    Article  CAS  PubMed  Google Scholar 

  79. Iijima K, Yoshizumi M, Ako J et al (1998) Expression of peroxisome proliferator-activated receptor gamma (PPARgamma) in rat aortic smooth muscle cells. Biochem Biophys Res Commun 247:353–356. https://doi.org/10.1006/bbrc.1998.8794

    Article  CAS  PubMed  Google Scholar 

  80. Gizard F, Amant C, Barbier O et al (2005) PPAR alpha inhibits vascular smooth muscle cell proliferation underlying intimal hyperplasia by inducing the tumor suppressor p16INK4a. J Clin Invest 115:3228–3238. https://doi.org/10.1172/JCI22756

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  81. Manea A, Manea S-A, Todirita A et al (2015) High-glucose-increased expression and activation of NADPH oxidase in human vascular smooth muscle cells is mediated by 4-hydroxynonenal-activated PPARα and PPARβ/δ. Cell Tissue Res 361:593–604. https://doi.org/10.1007/s00441-015-2120-0

    Article  CAS  PubMed  Google Scholar 

  82. Liu C, Bookout AL, Lee S et al (2014) PPARγ in vagal neurons regulates high-fat diet induced thermogenesis. Cell Metab 19:722–730. https://doi.org/10.1016/j.cmet.2014.01.021

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  83. Zoete V, Grosdidier A, Michielin O (2007) Peroxisome proliferator-activated receptor structures: ligand specificity, molecular switch and interactions with regulators. Biochim Biophys Acta 1771:915–925. https://doi.org/10.1016/j.bbalip.2007.01.007

    Article  CAS  PubMed  Google Scholar 

  84. O’Sullivan SE (2016) An update on PPAR activation by cannabinoids. Br J Pharmacol 173:1899–1910. https://doi.org/10.1111/bph.13497

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  85. Guellich A, Damy T, Conti M et al (2013) Tempol prevents cardiac oxidative damage and left ventricular dysfunction in the PPAR-α KO mouse. Am J Physiol Heart Circ Physiol 304:H1505–H1512. https://doi.org/10.1152/ajpheart.00669.2012

    Article  CAS  PubMed  Google Scholar 

  86. Duan SZ, Ivashchenko CY, Whitesall SE et al (2007) Hypotension, lipodystrophy, and insulin resistance in generalized PPARgamma-deficient mice rescued from embryonic lethality. J Clin Invest 117:812–822. https://doi.org/10.1172/JCI28859

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  87. Duan SZ, Usher MG, Mortensen RM (2009) PPARs: the vasculature, inflammation and hypertension. Curr Opin Nephrol Hypertens 18:128–133. https://doi.org/10.1097/MNH.0b013e328325803b

    Article  CAS  PubMed  Google Scholar 

  88. O’Sullivan SE, Kendall DA, Randall MD (2009) Time-dependent vascular effects of Endocannabinoids mediated by peroxisome proliferator-activated receptor gamma (PPARγ). PPAR Res 2009:425289–425299. https://doi.org/10.1155/2009/425289

    PubMed  PubMed Central  Google Scholar 

  89. Manning AM, Bell FP, Rosenbloom CL et al (1995) NF-kappa B is activated during acute inflammation in vivo in association with elevated endothelial cell adhesion molecule gene expression and leukocyte recruitment. J Inflamm 45:283–296

    CAS  PubMed  Google Scholar 

  90. d’Uscio LV, He T, Santhanam AVR et al (2014) Mechanisms of vascular dysfunction in mice with endothelium-specific deletion of the PPAR-δ gene. Am J Physiol Heart Circ Physiol 306:H1001–H1010. https://doi.org/10.1152/ajpheart.00761.2013

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  91. Li Y, Cheng L, Qin Q et al (2009) High-fat feeding in cardiomyocyte-restricted PPARdelta knockout mice leads to cardiac overexpression of lipid metabolic genes but fails to rescue cardiac phenotypes. J Mol Cell Cardiol 47:536–543. https://doi.org/10.1016/j.yjmcc.2009.07.001

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  92. Usuda D, Kanda T (2014) Peroxisome proliferator-activated receptors for hypertension. World J Cardiol 6:744–754. https://doi.org/10.4330/wjc.v6.i8.744

    Article  PubMed  PubMed Central  Google Scholar 

  93. Bradshaw HB, Walker JM (2005) The expanding field of cannabimimetic and related lipid mediators. Br J Pharmacol 144:459–465. https://doi.org/10.1038/sj.bjp.0706093

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  94. Lu H-C, Mackie K (2016) An Introduction to the endogenous cannabinoid system. Biol Psychiatr 79:516–525. https://doi.org/10.1016/j.biopsych.2015.07.028

    Article  CAS  Google Scholar 

  95. Heimann AS, Gomes I, Dale CS et al (2007) Hemopressin is an inverse agonist of CB1 cannabinoid receptors. Proc Natl Acad Sci USA 104:20588–20593. https://doi.org/10.1073/pnas.0706980105

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  96. Ben-Shabat S, Fride E, Sheskin T et al (1998) An entourage effect: inactive endogenous fatty acid glycerol esters enhance 2-arachidonoyl-glycerol cannabinoid activity. Eur J Pharmacol 353:23–31

    Article  CAS  PubMed  Google Scholar 

  97. Re G, Barbero R, Miolo A, Di Marzo V (2007) Palmitoylethanolamide, endocannabinoids and related cannabimimetic compounds in protection against tissue inflammation and pain: potential use in companion animals. Vet J 173:21–30. https://doi.org/10.1016/j.tvjl.2005.10.003

    Article  CAS  PubMed  Google Scholar 

  98. Bisogno T, Melck D, Bobrov MYu et al (2000) N-acyl-dopamines: novel synthetic CB(1) cannabinoid-receptor ligands and inhibitors of anandamide inactivation with cannabimimetic activity in vitro and in vivo. Biochem J 351(Pt 3):817–824

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  99. Björklund E, Norén E, Nilsson J, Fowler CJ (2010) Inhibition of monoacylglycerol lipase by troglitazone, N-arachidonoyl dopamine and the irreversible inhibitor JZL184: comparison of two different assays. Br J Pharmacol 161:1512–1526. https://doi.org/10.1111/j.1476-5381.2010.00974.x

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  100. Sugiura T, Kondo S, Sukagawa A et al (1995) 2-Arachidonoylglycerol: a possible endogenous cannabinoid receptor ligand in brain. Biochem Biophys Res Commun 215:89–97

    Article  CAS  PubMed  Google Scholar 

  101. Bisogno T, Berrendero F, Ambrosino G et al (1999) Brain regional distribution of endocannabinoids: implications for their biosynthesis and biological function. Biochem Biophys Res Commun 256:377–380. https://doi.org/10.1006/bbrc.1999.0254

    Article  CAS  PubMed  Google Scholar 

  102. Schmid PC, Schwartz KD, Smith CN et al (2000) A sensitive endocannabinoid assay. The simultaneous analysis of N-acylethanolamines and 2-monoacylglycerols. Chem Phys Lipids 104:185–191

    Article  CAS  PubMed  Google Scholar 

  103. Sugiura T, Kodaka T, Nakane S et al (1998) 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 243:838–843. https://doi.org/10.1006/bbrc.1998.8187

    Article  CAS  PubMed  Google Scholar 

  104. Di Marzo V (1999) Biosynthesis and inactivation of endocannabinoids: relevance to their proposed role as neuromodulators. Life Sci 65:645–655

    Article  PubMed  Google Scholar 

  105. Varga K, Wagner JA, Bridgen DT, Kunos G (1998) Platelet- and macrophage-derived endogenous cannabinoids are involved in endotoxin-induced hypotension. FASEB J 12:1035–1044

    Article  CAS  PubMed  Google Scholar 

  106. Murataeva N, Straiker A, Mackie K (2014) Parsing the players: 2-arachidonoylglycerol synthesis and degradation in the CNS. Br J Pharmacol 171:1379–1391. https://doi.org/10.1111/bph.12411

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  107. Blankman JL, Simon GM, Cravatt BF (2007) A comprehensive profile of brain enzymes that hydrolyze the endocannabinoid 2-arachidonoylglycerol. Chem Biol 14:1347–1356. https://doi.org/10.1016/j.chembiol.2007.11.006

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  108. Alhouayek M, Muccioli GG (2014) COX-2-derived endocannabinoid metabolites as novel inflammatory mediators. Trends Pharmacol Sci 35:284–292. https://doi.org/10.1016/j.tips.2014.03.001

    Article  CAS  PubMed  Google Scholar 

  109. Sugiura TT, Kondo SS, Kishimoto SS et al (2000) Evidence that 2-arachidonoylglycerol but not N-palmitoylethanolamine or anandamide is the physiological ligand for the cannabinoid CB2 receptor. Comparison of the agonistic activities of various cannabinoid receptor ligands in HL-60 cells. J Biol Chem 275:605–612

    Article  CAS  PubMed  Google Scholar 

  110. Járai Z, Wagner JA, Goparaju SK et al (2000) Cardiovascular effects of 2-arachidonoyl glycerol in anesthetized mice. Hypertension 35:679–684

    Article  PubMed  Google Scholar 

  111. Gao Y, Vasilyev DV, Goncalves MB et al (2010) Loss of retrograde endocannabinoid signaling and reduced adult neurogenesis in diacylglycerol lipase knock-out mice. J Neurosci 30:2017–2024. https://doi.org/10.1523/JNEUROSCI.5693-09.2010

    Article  CAS  PubMed  Google Scholar 

  112. Devane WAW, Hanus LL, Breuer AA et al (1992) Isolation and structure of a brain constituent that binds to the cannabinoid receptor. Science 258:1946–1949

    Article  CAS  PubMed  Google Scholar 

  113. Kury Al LT, Voitychuk OI, Yang K-HS et al (2014) Effects of the endogenous cannabinoid anandamide on voltage-dependent sodium and calcium channels in rat ventricular myocytes. Br J Pharmacol 171:3485–3498. https://doi.org/10.1111/bph.12734

    Article  CAS  Google Scholar 

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

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  115. Di Marzo V, De Petrocellis L, Sepe N, Buono A (1996) Biosynthesis of anandamide and related acylethanolamides in mouse J774 macrophages and N18 neuroblastoma cells. Biochem J 316(Pt 3):977–984

    Article  PubMed  PubMed Central  Google Scholar 

  116. Edgemond WS, Hillard CJ, Falck JR et al (1998) Human platelets and polymorphonuclear leukocytes synthesize oxygenated derivatives of arachidonylethanolamide (anandamide): their affinities for cannabinoid receptors and pathways of inactivation. Mol Pharmacol 54:180–188

    Article  CAS  PubMed  Google Scholar 

  117. Ishioka N, Bukoski RD (1999) A role for N-arachidonylethanolamine (anandamide) as the mediator of sensory nerve-dependent Ca2+ -induced relaxation. J Pharmacol Exp Ther 289:245–250

    CAS  PubMed  Google Scholar 

  118. Pacher P, Bátkai S, Kunos G (2006) The endocannabinoid system as an emerging target of pharmacotherapy. Pharmacol Rev 58:389–462. https://doi.org/10.1124/pr.58.3.2

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  119. Di Marzo VV, Fontana AA, Cadas HH et al (1994) Formation and inactivation of endogenous cannabinoid anandamide in central neurons. Nature 372:686–691. https://doi.org/10.1038/372686a0

    Article  PubMed  Google Scholar 

  120. Cravatt BF, Giang DK, Mayfield SP et al (1996) Molecular characterization of an enzyme that degrades neuromodulatory fatty-acid amides. Nature 384:83–87. https://doi.org/10.1038/384083a0

    Article  CAS  PubMed  Google Scholar 

  121. Tsuboi K, Sun Y-X, Okamoto Y et al (2005) Molecular characterization of N-acylethanolamine-hydrolyzing acid amidase, a novel member of the choloylglycine hydrolase family with structural and functional similarity to acid ceramidase. J Biol Chem 280:11082–11092. https://doi.org/10.1074/jbc.M413473200

    Article  CAS  PubMed  Google Scholar 

  122. Pertwee RG (2008) The diverse CB1 and CB2 receptor pharmacology of three plant cannabinoids: delta9-tetrahydrocannabinol, cannabidiol and delta9-tetrahydrocannabivarin. Br J Pharmacol 153:199–215. https://doi.org/10.1038/sj.bjp.0707442

    Article  CAS  PubMed  Google Scholar 

  123. Sun Y, Alexander SPH, Kendall DA, Bennett AJ (2006) Cannabinoids and PPARalpha signalling. Biochem Soc Trans 34:1095–1097. https://doi.org/10.1042/BST0341095

    Article  CAS  PubMed  Google Scholar 

  124. Bouaboula M, Hilairet S, Marchand J et al (2005) Anandamide induced PPARgamma transcriptional activation and 3T3-L1 preadipocyte differentiation. Eur J Pharmacol 517:174–181. https://doi.org/10.1016/j.ejphar.2005.05.032

    Article  CAS  PubMed  Google Scholar 

  125. Varga K, Lake K, Martin BR, Kunos G (1995) Novel antagonist implicates the CB1 cannabinoid receptor in the hypotensive action of anandamide. Eur J Pharmacol 278:279–283

    Article  CAS  PubMed  Google Scholar 

  126. Malinowska B, Kwolek G, Gothert M (2001) Anandamide and methanandamide induce both vanilloid VR1- and cannabinoid CB1 receptor-mediated changes in heart rate and blood pressure in anaesthetized rats. Naunyn Schmiedebergs Arch Pharmacol 364:562–569

    Article  CAS  PubMed  Google Scholar 

  127. Niehaus JL, Liu Y, Wallis KT et al (2007) CB1 cannabinoid receptor activity is modulated by the cannabinoid receptor interacting protein CRIP 1a. Mol Pharmacol 72:1557–1566. https://doi.org/10.1124/mol.107.039263

    Article  CAS  PubMed  Google Scholar 

  128. Di Marzo V, De Petrocellis L (2012) Why do cannabinoid receptors have more than one endogenous ligand? Philos Trans R Soc Lond B Biol Sci 367:3216–3228. https://doi.org/10.1098/rstb.2011.0382

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  129. Laprairie RB, Stahl EL, Bohn LM (2017) Approaches to assess biased signaling at the CB1R receptor. Methods Enzymol 593:259–279. https://doi.org/10.1016/bs.mie.2017.06.031

    Article  PubMed  Google Scholar 

  130. Laprairie RB, Bagher AM, Kelly MEM, Denovan-Wright EM (2016) Biased type 1 cannabinoid receptor signaling influences neuronal viability in a cell culture model of Huntington disease. Mol Pharmacol 89:364–375. https://doi.org/10.1124/mol.115.101980

    Article  CAS  PubMed  Google Scholar 

  131. Dhopeshwarkar A, Mackie K (2016) Functional selectivity of CB2 cannabinoid receptor ligands at a canonical and noncanonical pathway. J Pharmacol Exp Ther 358:342–351. https://doi.org/10.1124/jpet.116.232561

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  132. Chopra S, Baby C, Jacob JJ (2011) Neuro-endocrine regulation of blood pressure. Indian J Endocrinol Metab 15(Suppl 4):S281–S288. https://doi.org/10.4103/2230-8210.86860

    PubMed  PubMed Central  Google Scholar 

  133. Heesch CM (1999) Reflexes that control cardiovascular function. Am J Physiol 277:S234–S243

    CAS  PubMed  Google Scholar 

  134. Schmitz K, Mangels N, Häussler A et al (2016) Pro-inflammatory obesity in aged cannabinoid-2 receptor-deficient mice. Int J Obes (Lond) 40:366–379. https://doi.org/10.1038/ijo.2015.169

    Article  CAS  Google Scholar 

  135. Bátkai S, Pacher P, Osei-Hyiaman D et al (2004) Endocannabinoids acting at cannabinoid-1 receptors regulate cardiovascular function in hypertension. Circulation 110:1996–2002. https://doi.org/10.1161/01.CIR.0000143230.23252.D2

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  136. Guo Z, Liu Y-X, Yuan F et al (2015) Enhanced vasorelaxation effect of endogenous anandamide on thoracic aorta in renal vascular hypertension rats. Clin Exp Pharmacol Physiol 42:950–955. https://doi.org/10.1111/1440-1681.12450

    Article  CAS  Google Scholar 

  137. Li D, Chen B-M, Peng J et al (2009) Role of anandamide transporter in regulating calcitonin gene-related peptide production and blood pressure in hypertension. J Hypertens 27:1224–1232

    Article  CAS  PubMed  Google Scholar 

  138. Engeli S, Blüher M, Jumpertz R et al (2012) Circulating anandamide and blood pressure in patients with obstructive sleep apnea. J Hypertens 30:2345–2351. https://doi.org/10.1097/HJH.0b013e3283591595

    Article  CAS  PubMed  Google Scholar 

  139. Ho W-SV, Hill MN, Miller GE et al (2012) Serum contents of endocannabinoids are correlated with blood pressure in depressed women. Lipids Health Dis 11:32. https://doi.org/10.1186/1476-511X-11-32

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  140. Molvarec A, Fügedi G, Szabó E et al (2015) Decreased circulating anandamide levels in preeclampsia. Hypertens Res 38:413–418. https://doi.org/10.1038/hr.2015.20

    Article  CAS  PubMed  Google Scholar 

  141. Engeli S, Böhnke J, Feldpausch M et al (2005) Activation of the peripheral endocannabinoid system in human obesity. Diabetes 54:2838–2843

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  142. Ho W-SV, Gardiner SM (2009) Acute hypertension reveals depressor and vasodilator effects of cannabinoids in conscious rats. Br J Pharmacol 156:94–104. https://doi.org/10.1111/j.1476-5381.2008.00034.x

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  143. Wang Y, Kaminski NE, Wang DH (2005) VR1-mediated depressor effects during high-salt intake: role of anandamide. Hypertension 46:986–991. https://doi.org/10.1161/01.HYP.0000174596.95607.fd

    Article  CAS  PubMed  Google Scholar 

  144. Schaich CL, Grabenauer M, Thomas BF et al (2016) Medullary endocannabinoids contribute to the differential resting baroreflex sensitivity in rats with altered brain renin-angiotensin system expression. Front Physiol 7:207. https://doi.org/10.3389/fphys.2016.00207

    Article  PubMed  PubMed Central  Google Scholar 

  145. Szekeres M, Nádasy GL, Turu G et al (2012) Angiotensin II induces vascular endocannabinoid release, which attenuates its vasoconstrictor effect via CB1 cannabinoid receptors. J Biol Chem 287:31540–31550. https://doi.org/10.1074/jbc.M112.346296

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  146. Schaich CL, Shaltout HA, Brosnihan KB et al (2014) Acute and chronic systemic CB1 cannabinoid receptor blockade improves blood pressure regulation and metabolic profile in hypertensive (mRen2)27 rats. Physiol Rep 2:e12108. https://doi.org/10.14814/phy2.12108

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  147. Diep QN, Schiffrin EL (2001) Increased expression of peroxisome proliferator-activated receptor-alpha and -gamma in blood vessels of spontaneously hypertensive rats. Hypertension 38:249–254

    Article  CAS  PubMed  Google Scholar 

  148. Wilson JL, Duan R, El-Marakby A et al (2012) Peroxisome proliferator activated receptor-α agonist slows the progression of hypertension, attenuates plasma interleukin-6 levels and renal inflammatory markers in angiotensin II infused mice. PPAR Res 2012:645969–645977. https://doi.org/10.1155/2012/645969

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  149. Romero M, Jiménez R, Toral M et al (2016) Vascular and central activation of peroxisome proliferator-activated receptor-β attenuates angiotensin ii-induced hypertension: role of RGS-5. J Pharmacol Exp Ther 358:151–163. https://doi.org/10.1124/jpet.116.233106

    Article  CAS  PubMed  Google Scholar 

  150. Gao S, Park BM, Cha SA et al (2014) Comparision of secretagogue effects of rosiglitazone and telmisartan on ANP secretion in rats. Peptides 56:52–58. https://doi.org/10.1016/j.peptides.2014.03.014

    Article  CAS  PubMed  Google Scholar 

  151. Mendizábal VE, Adler-Graschinsky E (2007) Cannabinoids as therapeutic agents in cardiovascular disease: a tale of passions and illusions. Br J Pharmacol 151:427–440. https://doi.org/10.1038/sj.bjp.0707261

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  152. Christensen R, Kristensen PK, Bartels EM et al (2007) Efficacy and safety of the weight-loss drug rimonabant: a meta-analysis of randomised trials. Lancet 370:1706–1713. https://doi.org/10.1016/S0140-6736(07)61721-8

    Article  CAS  PubMed  Google Scholar 

  153. von Schaper E (2016) Bial incident raises FAAH suspicions. Nat Biotechnol 34:223. https://doi.org/10.1038/nbt0316-223a

    Article  CAS  Google Scholar 

  154. van Esbroeck ACM, Janssen APA, Cognetta AB et al (2017) Activity-based protein profiling reveals off-target proteins of the FAAH inhibitor BIA 10-2474. Science 356:1084–1087. https://doi.org/10.1126/science.aaf7497

    Article  PubMed  CAS  Google Scholar 

  155. Li GL, Winter H, Arends R et al (2012) Assessment of the pharmacology and tolerability of PF-04457845, an irreversible inhibitor of fatty acid amide hydrolase-1, in healthy subjects. Br J Clin Pharmacol 73:706–716. https://doi.org/10.1111/j.1365-2125.2011.04137.x

    Article  CAS  PubMed  Google Scholar 

  156. Jadoon KA, Tan GD, O’Sullivan SE (2017) A single dose of cannabidiol reduces blood pressure in healthy volunteers in a randomized crossover study. JCI Insight. https://doi.org/10.1172/jci.insight.93760

    PubMed  PubMed Central  Google Scholar 

  157. Hanus L, Breuer A, Tchilibon S et al (1999) HU-308: a specific agonist for CB(2), a peripheral cannabinoid receptor. Proc Natl Acad Sci USA 96:14228–14233

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  158. Reichenbach V, Ros J, Fernández-Varo G et al (2012) Prevention of fibrosis progression in CCl4-treated rats: role of the hepatic endocannabinoid and apelin systems. J Pharmacol Exp Ther 340:629–637. https://doi.org/10.1124/jpet.111.188078

    Article  CAS  PubMed  Google Scholar 

  159. Zhang M-J, Liu Y, Hu Z-C et al (2017) TRPV1 attenuates intracranial arteriole remodeling through inhibiting VSMC phenotypic modulation in hypertension. Histochem Cell Biol 147:511–521. https://doi.org/10.1007/s00418-016-1512-x

    Article  CAS  PubMed  Google Scholar 

  160. Song S, Ayon RJ, Yamamura A et al (2017) Capsaicin-induced Ca(2+) signaling is enhanced via upregulated TRPV1 channels in pulmonary artery smooth muscle cells from patients with idiopathic PAH. Am J Physiol Lung Cell Mol Physiol 312:L309–L325. https://doi.org/10.1152/ajplung.00357.2016

    Article  PubMed  Google Scholar 

  161. Pędzińska-Betiuk A, Weresa J, Toczek M et al (2017) Chronic inhibition of fatty acid amide hydrolase by URB597 produces differential effects on cardiac performance in normotensive and hypertensive rats. Br J Pharmacol 174:2114–2129. https://doi.org/10.1111/bph.13830

    Article  PubMed  CAS  Google Scholar 

  162. Gilbert K, Nian H, Yu C et al (2013) Fenofibrate lowers blood pressure in salt-sensitive but not salt-resistant hypertension. J Hypertens 31:820–829. https://doi.org/10.1097/HJH.0b013e32835e8227

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  163. Zarzuelo MJ, Jiménez R, Galindo P et al (2011) Antihypertensive effects of peroxisome proliferator-activated receptor-β activation in spontaneously hypertensive rats. Hypertension 58:733–743. https://doi.org/10.1161/HYPERTENSIONAHA.111.174490

    Article  CAS  PubMed  Google Scholar 

  164. Yu Y, Xue B-J, Wei S-G et al (2015) Activation of central PPAR-γ attenuates angiotensin II-induced hypertension. Hypertension 66:403–411. https://doi.org/10.1161/HYPERTENSIONAHA.115.05726

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  165. Füllert S, Schneider F, Haak E et al (2002) Effects of pioglitazone in nondiabetic patients with arterial hypertension: a double-blind, placebo-controlled study. J Clin Endocrinol Metab 87:5503–5506. https://doi.org/10.1210/jc.2002-020963

    Article  PubMed  CAS  Google Scholar 

  166. Zhang J, Liu X, Wang S-Q et al (2017) Identification of dual ligands targeting angiotensin II type 1 receptor and peroxisome proliferator-activated receptor-γ by core hopping of telmisartan. J Biomol Struct Dyn 35:2665–2680. https://doi.org/10.1080/07391102.2016.1227726

    Article  CAS  PubMed  Google Scholar 

  167. Toral M, Romero M, Pérez-Vizcaíno F et al (2017) Antihypertensive effects of peroxisome proliferator-activated receptor-β/δ activation. Am J Physiol Heart Circ Physiol 312:H189–H200. https://doi.org/10.1152/ajpheart.00155.2016

    Article  PubMed  Google Scholar 

  168. Seltzman HH, Shiner C, Hirt EE et al (2016) Peripherally selective cannabinoid 1 receptor (CB1R) agonists for the treatment of neuropathic pain. J Med Chem 59:7525–7543. https://doi.org/10.1021/acs.jmedchem.6b00516

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  169. Atwood BK, Mackie K (2010) CB2: a cannabinoid receptor with an identity crisis. Br J Pharmacol 160:467–479. https://doi.org/10.1111/j.1476-5381.2010.00729.x

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  170. Klabunde RE (2012) Introduction to the cardiovascular system. In: Cardiovascular physiology concepts. Lippincott Williams & Wilkins, pp 1–8

  171. Betts JG (2013) The cardiovascular system: blood vessels and circulation. In: Anatomy and physiology. OpenStax College, pp 837–903

  172. Sexton A, McDonald M, Cayla C et al (2007) 12-Lipoxygenase-derived eicosanoids protect against myocardial ischemia/reperfusion injury via activation of neuronal TRPV1. FASEB J 21:2695–2703. https://doi.org/10.1096/fj.06-7828com

    Article  CAS  PubMed  Google Scholar 

  173. Wagner JA, Hu K, Bauersachs J et al (2001) Endogenous cannabinoids mediate hypotension after experimental myocardial infarction. J Am Coll Cardiol 38:2048–2054

    Article  CAS  PubMed  Google Scholar 

  174. Maeda N, Osanai T, Kushibiki M et al (2009) Increased serum anandamide level at ruptured plaque site in patients with acute myocardial infarction. Fundam Clin Pharmacol 23:351–357. https://doi.org/10.1111/j.1472-8206.2009.00679.x

    Article  CAS  PubMed  Google Scholar 

  175. Wang P-F, Jiang L-S, Bu J et al (2012) Cannabinoid-2 receptor activation protects against infarct and ischemia-reperfusion heart injury. J Cardiovasc Pharmacol 59:301–307. https://doi.org/10.1097/FJC.0b013e3182418997

    Article  CAS  PubMed  Google Scholar 

  176. Liao Y, Bin J, Asakura M et al (2012) Deficiency of type 1 cannabinoid receptors worsens acute heart failure induced by pressure overload in mice. Eur Heart J 33:3124–3133. https://doi.org/10.1093/eurheartj/ehr246

    Article  CAS  PubMed  Google Scholar 

  177. Kola B, Hubina E, Tucci SA et al (2005) Cannabinoids and ghrelin have both central and peripheral metabolic and cardiac effects via AMP-activated protein kinase. J Biol Chem 280:25196–25201. https://doi.org/10.1074/jbc.C500175200

    Article  CAS  PubMed  Google Scholar 

  178. Di Filippo C, Rossi F, Rossi S, D’Amico M (2004) Cannabinoid CB2 receptor activation reduces mouse myocardial ischemia-reperfusion injury: involvement of cytokine/chemokines and PMN. J Leukoc Biol 75:453–459. https://doi.org/10.1189/jlb.0703303

    Article  PubMed  CAS  Google Scholar 

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

    Article  CAS  PubMed  Google Scholar 

  180. Huang W, Rubinstein J, Prieto AR et al (2009) Transient receptor potential vanilloid gene deletion exacerbates inflammation and atypical cardiac remodeling after myocardial infarction. Hypertension 53:243–250. https://doi.org/10.1161/HYPERTENSIONAHA.108.118349

    Article  CAS  PubMed  Google Scholar 

  181. Yue Tl TL, Chen J, Bao W et al (2001) In vivo myocardial protection from ischemia/reperfusion injury by the peroxisome proliferator-activated receptor-gamma agonist rosiglitazone. Circulation 104:2588–2594

    Article  CAS  PubMed  Google Scholar 

  182. Tabernero A, Schoonjans K, Jesel L et al (2002) Activation of the peroxisome proliferator-activated receptor alpha protects against myocardial ischaemic injury and improves endothelial vasodilatation. BMC Pharmacol 2:10. https://doi.org/10.1186/1471-2210-2-10

    Article  PubMed  PubMed Central  Google Scholar 

  183. Kapoor A, Collino M, Castiglia S et al (2010) Activation of peroxisome proliferator-activated receptor-beta/delta attenuates myocardial ischemia/reperfusion injury in the rat. Shock 34:117–124. https://doi.org/10.1097/SHK.0b013e3181cd86d6

    Article  CAS  PubMed  Google Scholar 

  184. Panayiotides IM (2015) What is the association of cannabis consumption and cardiovascular complications? Subst Abuse Res Treat 2015:1–3. https://doi.org/10.4137/SART.S21827

    Google Scholar 

  185. Goyal H, Awad HH, Ghali JK (2017) Role of cannabis in cardiovascular disorders. J Thorac Dis 9:2079–2092. https://doi.org/10.21037/jtd.2017.06.104

    Article  PubMed  PubMed Central  Google Scholar 

  186. Krylatov AV, Uzhachenko RV, Maslov LN et al (2002) Endogenous cannabinoids improve myocardial resistance to arrhythmogenic effects of coronary occlusion and reperfusion: a possible mechanism. Bull Exp Biol Med 133:122–124

    Article  CAS  PubMed  Google Scholar 

  187. Krylatov AV, Ugdyzhekova DS, Bernatskaya NA et al (2001) Activation of type II cannabinoid receptors improves myocardial tolerance to arrhythmogenic effects of coronary occlusion and reperfusion. Bull Exp Biol Med 131:523–525

    Article  CAS  PubMed  Google Scholar 

  188. Slavic S, Lauer D, Sommerfeld M et al (2013) Cannabinoid receptor 1 inhibition improves cardiac function and remodelling after myocardial infarction and in experimental metabolic syndrome. J Mol Med (Berl) 91:811–823. https://doi.org/10.1007/s00109-013-1034-0

    Article  CAS  Google Scholar 

  189. Gonca E, Darıcı F (2015) The effect of cannabidiol on ischemia/reperfusion-induced ventricular arrhythmias: the role of adenosine A1 receptors. J Cardiovasc Pharmacol Ther 20:76–83. https://doi.org/10.1177/1074248414532013

    Article  CAS  PubMed  Google Scholar 

  190. Montecucco F, Lenglet S, Braunersreuther V et al (2009) CB(2) cannabinoid receptor activation is cardioprotective in a mouse model of ischemia/reperfusion. J Mol Cell Cardiol 46:612–620. https://doi.org/10.1016/j.yjmcc.2008.12.014

    Article  CAS  PubMed  Google Scholar 

  191. Rang W-Q, Du Y-H, Hu C-P et al (2004) Protective effects of evodiamine on myocardial ischemia-reperfusion injury in rats. Planta Med 70:1140–1143. https://doi.org/10.1055/s-2004-835841

    Article  CAS  PubMed  Google Scholar 

  192. Qin S-L, Liu S-L, Wang R-R (2008) Protective effect of capsaicin on against myocardial ischemia-reperfusion injury of rat in vivo. Sichuan Da Xue Xue Bao Yi Xue Ban 39:550–554

    CAS  PubMed  Google Scholar 

  193. Dormandy JA, Charbonnel B, Eckland DJA et al (2005) Secondary prevention of macrovascular events in patients with type 2 diabetes in the PROactive Study (PROspective pioglitAzone Clinical Trial In macroVascular Events): a randomised controlled trial. Lancet 366:1279–1289. https://doi.org/10.1016/S0140-6736(05)67528-9

    Article  CAS  PubMed  Google Scholar 

  194. Zinman B, Wanner C, Lachin JM et al (2015) Empagliflozin, cardiovascular outcomes, and mortality in type 2 diabetes. N Engl J Med 373:2117–2128. https://doi.org/10.1056/NEJMoa1504720

    Article  CAS  PubMed  Google Scholar 

  195. Glukhova MA, Ornatsky OI, Frid MG et al (1987) Identification of smooth muscle-derived foam cells in the atherosclerotic plaque of human aorta with monoclonal antibody IIG10. Tissue Cell 19:657–663

    Article  CAS  PubMed  Google Scholar 

  196. Hansson GK, Hermansson A (2011) The immune system in atherosclerosis. Nat Immunol 12:204–212. https://doi.org/10.1038/ni.2001

    Article  CAS  PubMed  Google Scholar 

  197. Falk E, Fuster V (2017) Atherothrombosis: disease burden, activity, and vulnerability. Hurst’s the heart. McGraw-Hill Education, chap 32

  198. Garst C, Fulmer M, Thewke D, Brown S (2016) Optimized extraction of 2-arachidonyl glycerol and anandamide from aortic tissue and plasma for quantification by LC-MS/MS. Eur J Lipid Sci Technol 118:814–820. https://doi.org/10.1002/ejlt.201500115

    Article  CAS  PubMed  Google Scholar 

  199. Sugamura K, Sugiyama S, Nozaki T et al (2009) Activated endocannabinoid system in coronary artery disease and antiinflammatory effects of cannabinoid 1 receptor blockade on macrophages. Circulation 119:28–36. https://doi.org/10.1161/CIRCULATIONAHA.108.811992

    Article  CAS  PubMed  Google Scholar 

  200. Bátkai S, Rajesh M, Mukhopadhyay P et al (2007) Decreased age-related cardiac dysfunction, myocardial nitrative stress, inflammatory gene expression, and apoptosis in mice lacking fatty acid amide hydrolase. Am J Physiol Heart Circ Physiol 293:H909–H918. https://doi.org/10.1152/ajpheart.00373.2007

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  201. Vujic N, Schlager S, Eichmann TO et al (2016) Monoglyceride lipase deficiency modulates endocannabinoid signaling and improves plaque stability in ApoE-knockout mice. Atherosclerosis 244:9–21. https://doi.org/10.1016/j.atherosclerosis.2015.10.109

    Article  CAS  PubMed  Google Scholar 

  202. Tiyerili V, Zimmer S, Jung S et al (2010) CB1 receptor inhibition leads to decreased vascular AT1 receptor expression, inhibition of oxidative stress and improved endothelial function. Basic Res Cardiol 105:465–477. https://doi.org/10.1007/s00395-010-0090-7

    Article  CAS  PubMed  Google Scholar 

  203. Han KH, Lim S, Ryu J et al (2009) CB1 and CB2 cannabinoid receptors differentially regulate the production of reactive oxygen species by macrophages. Cardiovasc Res 84:378–386. https://doi.org/10.1093/cvr/cvp240

    Article  CAS  PubMed  Google Scholar 

  204. Jean-Gilles L, Braitch M, Latif ML et al (2015) Effects of pro-inflammatory cytokines on cannabinoid CB1 and CB2 receptors in immune cells. Acta Physiol (Oxf) 214:63–74. https://doi.org/10.1111/apha.12474

    Article  CAS  Google Scholar 

  205. Steffens S, Veillard NR, Arnaud C et al (2005) Low dose oral cannabinoid therapy reduces progression of atherosclerosis in mice. Nature 434:782–786. https://doi.org/10.1038/nature03389

    Article  CAS  PubMed  Google Scholar 

  206. Meletta R, Slavik R, Mu L et al (2017) Cannabinoid receptor type 2 (CB2) as one of the candidate genes in human carotid plaque imaging: evaluation of the novel radiotracer [(11)C]RS-016 targeting CB2 in atherosclerosis. Nucl Med Biol 47:31–43. https://doi.org/10.1016/j.nucmedbio.2017.01.001

    Article  CAS  PubMed  Google Scholar 

  207. Cao H, Wen G, Li H (2014) Role of peroxisome proliferator-activated receptor α in atherosclerosis. Mol Med Rep 9:1755–1760. https://doi.org/10.3892/mmr.2014.2020

    Article  CAS  PubMed  Google Scholar 

  208. Sueyoshi S, Mitsumata M, Kusumi Y et al (2010) Increased expression of peroxisome proliferator-activated receptor (PPAR)-alpha and PPAR-gamma in human atherosclerosis. Pathol Res Pract 206:429–438. https://doi.org/10.1016/j.prp.2010.01.010

    Article  CAS  PubMed  Google Scholar 

  209. Taketa K, Matsumura T, Yano M et al (2008) Oxidized low density lipoprotein activates peroxisome proliferator-activated receptor-alpha (PPARalpha) and PPARgamma through MAPK-dependent COX-2 expression in macrophages. J Biol Chem 283:9852–9862. https://doi.org/10.1074/jbc.M703318200

    Article  CAS  PubMed  Google Scholar 

  210. Giaginis C, Klonaris C, Katsargyris A et al (2011) Correlation of peroxisome proliferator-activated receptor-gamma (PPAR-gamma) and retinoid X receptor-alpha (RXR-alpha) expression with clinical risk factors in patients with advanced carotid atherosclerosis. Med Sci Monit 17:381–391. https://doi.org/10.12659/MSM.881849

    Google Scholar 

  211. Nissen SE, Nicholls SJ, Wolski K et al (2008) Effect of rimonabant on progression of atherosclerosis in patients with abdominal obesity and coronary artery disease: the STRADIVARIUS randomized controlled trial. JAMA 299:1547–1560. https://doi.org/10.1001/jama.299.13.1547

    Article  CAS  PubMed  Google Scholar 

  212. O’Leary DH, Reuwer AQ, Nissen SE et al (2011) Effect of rimonabant on carotid intima-media thickness (CIMT) progression in patients with abdominal obesity and metabolic syndrome: the AUDITOR trial. Heart 97:1143–1150. https://doi.org/10.1136/hrt.2011.223446

    Article  PubMed  CAS  Google Scholar 

  213. Rajesh M, Mukhopadhyay P, Haskó G et al (2010) Cannabinoid-1 receptor activation induces reactive oxygen species-dependent and -independent mitogen-activated protein kinase activation and cell death in human coronary artery endothelial cells. Br J Pharmacol 160:688–700. https://doi.org/10.1111/j.1476-5381.2010.00712.x

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  214. Rajesh M, Mukhopadhyay P, Bátkai S et al (2007) CB2-receptor stimulation attenuates TNF-alpha-induced human endothelial cell activation, transendothelial migration of monocytes, and monocyte-endothelial adhesion. Am J Physiol Heart Circ Physiol 293:H2210–H2218. https://doi.org/10.1152/ajpheart.00688.2007

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  215. Singla S, Sachdeva R, Mehta JL (2012) Cannabinoids and atherosclerotic coronary heart disease. Clin Cardiol 35:329–335. https://doi.org/10.1002/clc.21962

    Article  PubMed  Google Scholar 

  216. Yuan M, Kiertscher SM, Cheng Q et al (2002) Delta 9-Tetrahydrocannabinol regulates Th1/Th2 cytokine balance in activated human T cells. J Neuroimmunol 133:124–131

    Article  CAS  PubMed  Google Scholar 

  217. Wang Y, Cui L, Xu H et al (2017) TRPV1 agonism inhibits endothelial cell inflammation via activation of eNOS/NO pathway. Atherosclerosis 260:13–19. https://doi.org/10.1016/j.atherosclerosis.2017.03.016

    Article  CAS  PubMed  Google Scholar 

  218. Marx N, Kehrle B, Kohlhammer K et al (2002) PPAR activators as antiinflammatory mediators in human T lymphocytes: implications for atherosclerosis and transplantation-associated arteriosclerosis. Circ Res 90:703–710

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  219. Li AC, Binder CJ, Gutierrez A et al (2004) Differential inhibition of macrophage foam-cell formation and atherosclerosis in mice by PPARalpha, beta/delta, and gamma. J Clin Invest 114:1564–1576. https://doi.org/10.1172/JCI18730

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  220. Babaev VR, Ishiguro H, Ding L et al (2007) Macrophage expression of peroxisome proliferator-activated receptor-alpha reduces atherosclerosis in low-density lipoprotein receptor-deficient mice. Circulation 116:1404–1412. https://doi.org/10.1161/CIRCULATIONAHA.106.684704

    Article  CAS  PubMed  Google Scholar 

  221. Derosa G, Sahebkar A, Maffioli P (2017) The role of various peroxisome proliferator-activated receptors and their ligands in clinical practice. J Cell Physiol 362:1563. https://doi.org/10.1002/jcp.25804

    Google Scholar 

  222. Petrucci V, Chicca A, Glasmacher S et al (2017) Pepcan-12 (RVD-hemopressin) is a CB2 receptor positive allosteric modulator constitutively secreted by adrenals and in liver upon tissue damage. Sci Rep 7:9560. https://doi.org/10.1038/s41598-017-09808-8

    Article  PubMed  PubMed Central  Google Scholar 

  223. Martin BR, Wiley JL, Beletskaya I et al (2006) Pharmacological characterization of novel water-soluble cannabinoids. J Pharmacol Exp Ther 318:1230–1239. https://doi.org/10.1124/jpet.106.104109

    Article  CAS  PubMed  Google Scholar 

  224. Rozenfeld RR, Gupta AA, Gagnidze KK et al (2011) AT1R-CB1R heteromerization reveals a new mechanism for the pathogenic properties of angiotensin II. EMBO J 30:2350–2363. https://doi.org/10.1038/emboj.2011.139

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  225. Sierra S, Gomes I, Devi LA (2017) Class A GPCRs: cannabinoid and opioid receptor heteromers. G-Protein-Coupled Receptor Dimers. Springer International Publishing, Cham, pp 173–206

    Chapter  Google Scholar 

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Acknowledgements

We thank Jill K Gregory, MFA, CMI for designing illustrations and Dr. Guillermo Sánchez-Elvira for critical reading of the manuscript.

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  1. Salvador Sierra

    Present address: Department of Physiology and Biophysics, Molecular Medicine Research Building, Virginia Commonwealth University, 1220 East Broad Street, Richmond, VA, 23298, USA

Authors and Affiliations

  1. Department of Pharmacological Sciences, Icahn School of Medicine at Mount Sinai, New York, NY, USA

    Salvador Sierra

  2. Department of Medical Genomics, Royal Prince Alfred Hospital, Sydney, Australia

    Natasha Luquin

  3. Neurology Service, Electromyography, Motor Control and Neuropathic Pain Unit, Hospital Clínic de Barcelona, University of Barcelona, Barcelona, Spain

    Judith Navarro-Otano

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S.S. salary is supported by a Grant from Alfonso Martín Escudero Foundation.

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Sierra, S., Luquin, N. & Navarro-Otano, J. The endocannabinoid system in cardiovascular function: novel insights and clinical implications. Clin Auton Res 28, 35–52 (2018). https://doi.org/10.1007/s10286-017-0488-5

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