Endocannabinoid Signalling in Atherosclerosis and Related Metabolic Complications

Raquel Guillamat-Prats; Martina Rami; Stephan Herzig; Sabine Steffens

doi:10.1055/s-0039-1678738

Thrombosis and Haemostasis, Table of Contents

Thromb Haemost 2019; 119(04): 567-575
DOI: 10.1055/s-0039-1678738

Theme Issue Article

Georg Thieme Verlag KG Stuttgart · New York

Endocannabinoid Signalling in Atherosclerosis and Related Metabolic Complications

Authors

Raquel Guillamat-Prats

¹Institute for Cardiovascular Prevention (IPEK), Ludwig-Maximilians-University (LMU) Munich, Munich, Germany
Martina Rami

¹Institute for Cardiovascular Prevention (IPEK), Ludwig-Maximilians-University (LMU) Munich, Munich, Germany
Stephan Herzig

²Institute for Diabetes and Cancer, Helmholtz Center Munich, Neuherberg, Germany

³Joint Heidelberg-IDC Translational Diabetes Program, Inner Medicine I, Heidelberg University Hospital, Heidelberg, Germany

⁴Molecular Metabolic Control, Technical University Munich, Munich, Germany
Sabine Steffens

¹Institute for Cardiovascular Prevention (IPEK), Ludwig-Maximilians-University (LMU) Munich, Munich, Germany

⁵German Centre for Cardiovascular Research (DZHK), Partner Site Munich Heart Alliance, Munich, Germany

Abstract

Endocannabinoids are a group of arachidonic acid-derived lipid mediators binding to cannabinoid receptors CB1 and CB2. An overactivity of the endocannabinoid system plays a pathophysiological role in the development of visceral obesity and insulin resistance. Moreover, elevated circulating endocannabinoid levels are also prevalent in atherosclerosis. The pathophysiological increase of endocannabinoid levels is due to an altered expression of endocannabinoid synthesizing and degrading enzymes induced by inflammatory mediators such as cytokines or lipids. Emerging experimental evidence suggests that enhanced endocannabinoid signalling affects atherosclerosis via multiple effects, including a modulation of vascular inflammation, leukocyte recruitment, macrophage cholesterol metabolism and consequently atherosclerotic plaque stability. In addition, recent findings in various metabolic disease models highlight the relevance of peripheral CB1 cannabinoid receptors in adipose tissue, liver and pancreas, which crucially regulate lipid and glucose metabolism as well as macrophage properties in these organs. This suggests that targeting the endocannabinoid system in the vasculature and peripheral organs might have a therapeutic potential for atherosclerosis by inhibiting vascular inflammation and improving metabolic risk factors. This review will provide a brief update on the effects of endocannabinoid signalling in atherosclerosis and related metabolic complications.

Keywords

atherosclerosis - inflammation - lipid mediators - metabolic disorders - obesity

Full Text

References

References
1 Ogden CL, Carroll MD, Kit BK, Flegal KM. Prevalence of childhood and adult obesity in the United States, 2011–2012. JAMA 2014; 311 (08) 806-814
2 Inoue Y, Qin B, Poti J, Sokol R, Gordon-Larsen P. Epidemiology of obesity in adults: latest trends. Curr Obes Rep 2018; 7 (04) 276-288
3 Finucane MM, Stevens GA, Cowan MJ. , et al; Global Burden of Metabolic Risk Factors of Chronic Diseases Collaborating Group (Body Mass Index). National, regional, and global trends in body-mass index since 1980: systematic analysis of health examination surveys and epidemiological studies with 960 country-years and 9·1 million participants. Lancet 2011; 377 (9765): 557-567
4 Collaboration NRF. ; NCD Risk Factor Collaboration (NCD-RisC). Trends in adult body-mass index in 200 countries from 1975 to 2014: a pooled analysis of 1698 population-based measurement studies with 19·2 million participants. Lancet 2016; 387 (10026): 1377-1396
5 World Health Organization. Obesity and overweight. Available at: https://www.who.int/news-room/fact-sheets/detail/obesity-and-overweight
6 Tchernof A, Després JP. Pathophysiology of human visceral obesity: an update. Physiol Rev 2013; 93 (01) 359-404
7 Skinner AC, Perrin EM, Moss LA, Skelton JA. Cardiometabolic risks and severity of obesity in children and young adults. N Engl J Med 2015; 373 (14) 1307-1317
8 Di Marzo V, Matias I. Endocannabinoid control of food intake and energy balance. Nat Neurosci 2005; 8 (05) 585-589
9 Szmitko PE, Verma S. The endocannabinoid system and cardiometabolic risk. Atherosclerosis 2008; 199 (02) 248-256
10 Pacher P, Steffens S. The emerging role of the endocannabinoid system in cardiovascular disease. Semin Immunopathol 2009; 31 (01) 63-77
11 Valenta I, Varga ZV, Valentine H. , et al. Feasibility evaluation of myocardial cannabinoid type 1 receptor imaging in obesity: a translational approach. JACC Cardiovasc Imaging 2018; 11 (2, Pt 2): 320-332
12 van Eenige R, van der Stelt M, Rensen PCN, Kooijman S. Regulation of adipose tissue metabolism by the endocannabinoid system. Trends Endocrinol Metab 2018; 29 (05) 326-337
13 Di Marzo V, Després JP. CB1 antagonists for obesity--what lessons have we learned from rimonabant?. Nat Rev Endocrinol 2009; 5 (11) 633-638
14 Pacher P, Steffens S, Haskó G, Schindler TH, Kunos G. Cardiovascular effects of marijuana and synthetic cannabinoids: the good, the bad, and the ugly. Nat Rev Cardiol 2018; 15 (03) 151-166
15 Console-Bram L, Marcu J, Abood ME. Cannabinoid receptors: nomenclature and pharmacological principles. Prog Neuropsychopharmacol Biol Psychiatry 2012; 38 (01) 4-15
16 Irving A, Abdulrazzaq G, Chan SLF, Penman J, Harvey J, Alexander SPH. Cannabinoid receptor-related Orphan G protein-coupled receptors. Adv Pharmacol 2017; 80: 223-247
17 Sugamura K, Sugiyama S, Nozaki T. , et al. Activated endocannabinoid system in coronary artery disease and antiinflammatory effects of cannabinoid 1 receptor blockade on macrophages. Circulation 2009; 119 (01) 28-36
18 Engeli S, Böhnke J, Feldpausch M. , et al. Activation of the peripheral endocannabinoid system in human obesity. Diabetes 2005; 54 (10) 2838-2843
19 Blüher M, Engeli S, Klöting N. , et al. Dysregulation of the peripheral and adipose tissue endocannabinoid system in human abdominal obesity. Diabetes 2006; 55 (11) 3053-3060
20 Côté M, Matias I, Lemieux I. , et al. Circulating endocannabinoid levels, abdominal adiposity and related cardiometabolic risk factors in obese men. Int J Obes 2007; 31 (04) 692-699
21 Quercioli A, Pataky Z, Montecucco F. , et al. Coronary vasomotor control in obesity and morbid obesity: contrasting flow responses with endocannabinoids, leptin, and inflammation. JACC Cardiovasc Imaging 2012; 5 (08) 805-815
22 Quercioli A, Pataky Z, Vincenti G. , et al. Elevated endocannabinoid plasma levels are associated with coronary circulatory dysfunction in obesity. Eur Heart J 2011; 32 (11) 1369-1378
23 Cappellano G, Uberti F, Caimmi PP. , et al. Different expression and function of the endocannabinoid system in human epicardial adipose tissue in relation to heart disease. Can J Cardiol 2013; 29 (04) 499-509
24 Pacher P. Cannabinoid CB1 receptor antagonists for atherosclerosis and cardiometabolic disorders: new hopes, old concerns?. Arterioscler Thromb Vasc Biol 2009; 29 (01) 7-9
25 Van Gaal LF, Scheen AJ, Rissanen AM, Rössner S, Hanotin C, Ziegler O. ; RIO-Europe Study Group. Long-term effect of CB1 blockade with rimonabant on cardiometabolic risk factors: two year results from the RIO-Europe Study. Eur Heart J 2008; 29 (14) 1761-1771
26 Libby P, Ridker PM, Hansson GK. Progress and challenges in translating the biology of atherosclerosis. Nature 2011; 473 (7347): 317-325
27 Li H, Förstermann U. Nitric oxide in the pathogenesis of vascular disease. J Pathol 2000; 190 (03) 244-254
28 Moore KJ, Sheedy FJ, Fisher EA. Macrophages in atherosclerosis: a dynamic balance. Nat Rev Immunol 2013; 13 (10) 709-721
29 Tiyerili V, Zimmer S, Jung S. , et al. CB1 receptor inhibition leads to decreased vascular AT1 receptor expression, inhibition of oxidative stress and improved endothelial function. Basic Res Cardiol 2010; 105 (04) 465-477
30 Mukhopadhyay P, Pan H, Rajesh M. , et al. CB1 cannabinoid receptors promote oxidative/nitrosative stress, inflammation and cell death in a murine nephropathy model. Br J Pharmacol 2010; 160 (03) 657-668
31 Dol-Gleizes F, Paumelle R, Visentin V. , et al. Rimonabant, a selective cannabinoid CB1 receptor antagonist, inhibits atherosclerosis in LDL receptor-deficient mice. Arterioscler Thromb Vasc Biol 2009; 29 (01) 12-18
32 Steffens S, Veillard NR, Arnaud C. , et al. Low dose oral cannabinoid therapy reduces progression of atherosclerosis in mice. Nature 2005; 434 (7034): 782-786
33 Zhao Y, Liu Y, Zhang W. , et al. WIN55212-2 ameliorates atherosclerosis associated with suppression of pro-inflammatory responses in ApoE-knockout mice. Eur J Pharmacol 2010; 649 (1–3): 285-292
34 Zhao Y, Yuan Z, Liu Y. , et al. Activation of cannabinoid CB2 receptor ameliorates atherosclerosis associated with suppression of adhesion molecules. J Cardiovasc Pharmacol 2010; 55 (03) 292-298
35 Hoyer FF, Steinmetz M, Zimmer S. , et al. Atheroprotection via cannabinoid receptor-2 is mediated by circulating and vascular cells in vivo. J Mol Cell Cardiol 2011; 51 (06) 1007-1014
36 Netherland CD, Pickle TG, Bales A, Thewke DP. Cannabinoid receptor type 2 (CB2) deficiency alters atherosclerotic lesion formation in hyperlipidemic Ldlr-null mice. Atherosclerosis 2010; 213 (01) 102-108
37 Willecke F, Zeschky K, Ortiz Rodriguez A. , et al. Cannabinoid receptor 2 signaling does not modulate atherogenesis in mice. PLoS One 2011; 6 (04) e19405
38 Rajesh M, Mukhopadhyay P, Bátkai S. , et al. 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 2007; 293 (04) H2210-H2218
39 Rajesh M, Mukhopadhyay P, Haskó G, Huffman JW, Mackie K, Pacher P. CB2 cannabinoid receptor agonists attenuate TNF-alpha-induced human vascular smooth muscle cell proliferation and migration. Br J Pharmacol 2008; 153 (02) 347-357
40 Lenglet S, Thomas A, Soehnlein O. , et al. Fatty acid amide hydrolase deficiency enhances intraplaque neutrophil recruitment in atherosclerotic mice. Arterioscler Thromb Vasc Biol 2013; 33 (02) 215-223
41 Hoyer FF, Khoury M, Slomka H. , 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
42 Molica F, Burger F, Thomas A. , et al. Endogenous cannabinoid receptor CB1 activation promotes vascular smooth-muscle cell proliferation and neointima formation. J Lipid Res 2013; 54 (05) 1360-1368
43 Vujic N, Schlager S, Eichmann TO. , et al. Monoglyceride lipase deficiency modulates endocannabinoid signaling and improves plaque stability in ApoE-knockout mice. Atherosclerosis 2016; 244: 9-21
44 Montecucco F, Di Marzo V, da Silva RF. , et al. The activation of the cannabinoid receptor type 2 reduces neutrophilic protease-mediated vulnerability in atherosclerotic plaques. Eur Heart J 2012; 33 (07) 846-856
45 Jehle J, Schöne B, Bagheri S. , et al. Elevated levels of 2-arachidonoylglycerol promote atherogenesis in ApoE-/- mice. PLoS One 2018; 13 (05) e0197751
46 Guillamat Prats R, Rami M, Ring L. , et al. Deficiency of monoacylglycerol lipase enhances IgM plasma levels and limits atherogenesis in a CB2-dependent manner. Thromb Haemost 2019; 119 (02) 348-351
47 Grabner GF, Zimmermann R, Schicho R, Taschler U. Monoglyceride lipase as a drug target: at the crossroads of arachidonic acid metabolism and endocannabinoid signaling. Pharmacol Ther 2017; 175: 35-46
48 Schlosburg JE, Blankman JL, Long JZ. , et al. Chronic monoacylglycerol lipase blockade causes functional antagonism of the endocannabinoid system. Nat Neurosci 2010; 13 (09) 1113-1119
49 Taschler U, Eichmann TO, Radner FPW. , et al. Monoglyceride lipase deficiency causes desensitization of intestinal cannabinoid receptor type 1 and increased colonic μ-opioid receptor sensitivity. Br J Pharmacol 2015; 172 (17) 4419-4429
50 Kinsey SG, Wise LE, Ramesh D. , et al. Repeated low-dose administration of the monoacylglycerol lipase inhibitor JZL184 retains cannabinoid receptor type 1-mediated antinociceptive and gastroprotective effects. J Pharmacol Exp Ther 2013; 345 (03) 492-501
51 Jehle J, Hoyer FF, Schöne B. , et al. Myeloid-specific deletion of diacylglycerol lipase α inhibits atherogenesis in ApoE-deficient mice. PLoS One 2016; 11 (01) e0146267
52 Gao Y, Vasilyev DV, Goncalves MB. , et al. Loss of retrograde endocannabinoid signaling and reduced adult neurogenesis in diacylglycerol lipase knock-out mice. J Neurosci 2010; 30 (06) 2017-2024
53 Ryberg E, Larsson N, Sjögren S. , et al. The orphan receptor GPR55 is a novel cannabinoid receptor. Br J Pharmacol 2007; 152 (07) 1092-1101
54 Ross RA. L-α-lysophosphatidylinositol meets GPR55: a deadly relationship. Trends Pharmacol Sci 2011; 32 (05) 265-269
55 Chiurchiù V, Lanuti M, De Bardi M, Battistini L, Maccarrone M. The differential characterization of GPR55 receptor in human peripheral blood reveals a distinctive expression in monocytes and NK cells and a proinflammatory role in these innate cells. Int Immunol 2015; 27 (03) 153-160
56 Lanuti M, Talamonti E, Maccarrone M, Chiurchiù V. Activation of GPR55 receptors exacerbates oxLDL-induced lipid accumulation and inflammatory responses, while reducing cholesterol efflux from human macrophages. PLoS One 2015; 10 (05) e0126839
57 Montecucco F, Bondarenko AI, Lenglet S. , et al. Treatment with the GPR55 antagonist CID16020046 increases neutrophil activation in mouse atherogenesis. Thromb Haemost 2016; 116 (05) 987-997
58 Rinne P, Guillamat-Prats R, Rami M. , et al. Palmitoylethanolamide promotes a proresolving macrophage phenotype and attenuates atherosclerotic plaque formation. Arterioscler Thromb Vasc Biol 2018; 38 (11) 2562-2575
59 Vujic N, Korbelius M, Leopold C. , et al. Monoglyceride lipase deficiency affects hepatic cholesterol metabolism and lipid-dependent gut transit in ApoE-/- mice. Oncotarget 2017; 8 (20) 33122-33136
60 Montecucco F, Matias I, Lenglet S. , et al. Regulation and possible role of endocannabinoids and related mediators in hypercholesterolemic mice with atherosclerosis. Atherosclerosis 2009; 205 (02) 433-441
61 Chanda D, Kim YH, Li T. , et al. Hepatic cannabinoid receptor type 1 mediates alcohol-induced regulation of bile acid enzyme genes expression via CREBH. PLoS One 2013; 8 (07) e68845
62 Osei-Hyiaman D, DePetrillo M, Pacher P. , et al. Endocannabinoid activation at hepatic CB1 receptors stimulates fatty acid synthesis and contributes to diet-induced obesity. J Clin Invest 2005; 115 (05) 1298-1305
63 Haas MJ, Mazza AD, Wong NC, Mooradian AD. Inhibition of apolipoprotein A-I gene expression by obesity-associated endocannabinoids. Obesity (Silver Spring) 2012; 20 (04) 721-729
64 Ruby MA, Nomura DK, Hudak CS. , et al. Overactive endocannabinoid signaling impairs apolipoprotein E-mediated clearance of triglyceride-rich lipoproteins. Proc Natl Acad Sci U S A 2008; 105 (38) 14561-14566
65 Jiang LS, Pu J, Han ZH, Hu LH, He B. Role of activated endocannabinoid system in regulation of cellular cholesterol metabolism in macrophages. Cardiovasc Res 2009; 81 (04) 805-813
66 Duewell P, Kono H, Rayner KJ. , et al. NLRP3 inflammasomes are required for atherogenesis and activated by cholesterol crystals. Nature 2010; 464 (7293): 1357-1361
67 Jourdan T, Godlewski G, Cinar R. , et al. Activation of the Nlrp3 inflammasome in infiltrating macrophages by endocannabinoids mediates beta cell loss in type 2 diabetes. Nat Med 2013; 19 (09) 1132-1140
68 Rayner KJ. Cell death in the vessel wall: the good, the bad, the ugly. Arterioscler Thromb Vasc Biol 2017; 37 (07) e75-e81
69 Freeman-Anderson NE, Pickle TG, Netherland CD, Bales A, Buckley NE, Thewke DP. Cannabinoid (CB2) receptor deficiency reduces the susceptibility of macrophages to oxidized LDL/oxysterol-induced apoptosis. J Lipid Res 2008; 49 (11) 2338-2346
70 Tam J, Vemuri VK, Liu J. , et al. Peripheral CB1 cannabinoid receptor blockade improves cardiometabolic risk in mouse models of obesity. J Clin Invest 2010; 120 (08) 2953-2966
71 Bowles NP, Karatsoreos IN, Li X. , et al. A peripheral endocannabinoid mechanism contributes to glucocorticoid-mediated metabolic syndrome. Proc Natl Acad Sci U S A 2015; 112 (01) 285-290
72 Jourdan T, Szanda G, Rosenberg AZ. , et al. Overactive cannabinoid 1 receptor in podocytes drives type 2 diabetic nephropathy. Proc Natl Acad Sci U S A 2014; 111 (50) E5420-E5428
73 Gruden G, Barutta F, Kunos G, Pacher P. Role of the endocannabinoid system in diabetes and diabetic complications. Br J Pharmacol 2016; 173 (07) 1116-1127
74 Silvestri C, Di Marzo V. Second generation CB1 receptor blockers and other inhibitors of peripheral endocannabinoid overactivity and the rationale of their use against metabolic disorders. Expert Opin Investig Drugs 2012; 21 (09) 1309-1322
75 Kunos G, Osei-Hyiaman D, Bátkai S, Sharkey KA, Makriyannis A. Should peripheral CB(1) cannabinoid receptors be selectively targeted for therapeutic gain?. Trends Pharmacol Sci 2009; 30 (01) 1-7
76 Ruiz de Azua I, Mancini G, Srivastava RK. , et al. Adipocyte cannabinoid receptor CB1 regulates energy homeostasis and alternatively activated macrophages. J Clin Invest 2017; 127 (11) 4148-4162
77 Jourdan T, Park JK, Varga ZV. , et al. Cannabinoid-1 receptor deletion in podocytes mitigates both glomerular and tubular dysfunction in a mouse model of diabetic nephropathy. Diabetes Obes Metab 2018; 20 (03) 698-708