Cannabinoid CB 1 Receptor Antagonists for Atherosclerosis and Cardiometabolic Disorders
2008; Lippincott Williams & Wilkins; Volume: 29; Issue: 1 Linguagem: Inglês
10.1161/atvbaha.108.178129
ISSN1524-4636
Autores Tópico(s)Dietary Effects on Health
ResumoHomeArteriosclerosis, Thrombosis, and Vascular BiologyVol. 29, No. 1Cannabinoid CB1 Receptor Antagonists for Atherosclerosis and Cardiometabolic Disorders Free AccessEditorialPDF/EPUBAboutView PDFView EPUBSections ToolsAdd to favoritesDownload citationsTrack citationsPermissions ShareShare onFacebookTwitterLinked InMendeleyReddit Jump toFree AccessEditorialPDF/EPUBCannabinoid CB1 Receptor Antagonists for Atherosclerosis and Cardiometabolic DisordersNew Hopes, Old Concerns? Pál Pacher Pál PacherPál Pacher From the Sections on Oxidative Stress Tissue Injury, Laboratory of Physiological Studies, NIAAA, National Institutes of Health, Bethesda, Md. Originally published1 Jan 2009https://doi.org/10.1161/ATVBAHA.108.178129Arteriosclerosis, Thrombosis, and Vascular Biology. 2009;29:7–9The endocannabinoid system (EC) system is a recently characterized physiological system that comprises the G protein–coupled CB1 and CB2, as well as additional yet unidentified receptors, their endogenous ligands termed endocannabinoids (lipid mediators generated in the brain and peripheral tissues, which elicit a broad range of biological effects similar to those of marijuana), and the enzymes and membrane transporter(s) involved in the biosynthesis/degradation and cellular uptake/release of these lipid mediators.1 The dysregulation of the endocannabinoid system has recently been implicated in numerous human diseases, and its pharmacological modulation is a very promising strategy to treat various inflammatory, neurodegenerative, cardiovascular, metabolic disorders, ischemia/reperfusion damage, as well as cancer and pain.1,2 CB2 receptors are predominantly expressed in immune and hematopoietic cells, but to a lesser extent also in the myocardium, and in coronary endothelial and smooth muscle cells.1,3 Activation of CB2 receptors mediates various antiinflammatory and immunosuppressive effects,1 and has recently been shown to attenuate atherosclerosis progression in an apolipoprotein E knockout mouse model of the disease, presumably by reducing the proliferative capacity and interferon (INF)-γ production of lymphoid cells, and inhibiting macrophage chemotaxis and migration.4 CB2 receptors activation also attenuates the tumor necrosis factor (TNF)-α– or bacterial endotoxin (lipopolysaccharide [LPS])-induced vascular inflammatory response, and inflammation associated with ischemic reperfusion injury.3,5 The CB1 receptor is widely distributed in the central nervous system and at lower levels in various peripheral tissues (eg, myocardium, adipose tissue, liver, etc), and it has been shown to play an important role in regulating body weight, energy balance, as well as glucose and lipid/fat metabolism.1,2 Tonic activation of CB1 receptors by endocannabinoids may also contribute to cardiovascular risk factors in patients with obesity/metabolic syndrome and diabetes, such as plasma lipid alterations, abdominal obesity, hepatic steatosis, and insulin and leptin resistance,6–11 through mechanisms that have not yet been fully explored.3 Endocannabinoids acting via CB1 receptors have also been implicated in the hypotension and decreased cardiac contractility associated with various forms of shock and heart failure, whereas its tonic activation in hypertension may be a homeostatic mechanism counteracting the increase in arterial pressure.3See accompanying article on page 12Clinical trials with rimonabant (the first CB1 antagonist/inverse agonist) approved in numerous European and other countries, for the treatment of obesity and associated cardio-metabolic disorders) involving obese individuals with the metabolic syndrome or type 2 diabetes, suggest multiple beneficial effects of chronic CB1 blockade on plasma triglyceride, HDL cholesterol levels, glucose tolerance, and markers of inflammation (eg, C reactive protein), in addition to the reduction of body weight and waist circumference.6–9,11,12 The effects of rimonabant on these secondary end points could only partly be explained by weight loss, suggesting that rimonabant has additional metabolic or protective effects leading to a further decrease in cardiometabolic risk factors. Although, the results of the recent STRADIVARIUS trial demonstrating only modest improvements in the normalized total atheroma volume but no difference in the percent atheroma volume in patient with coronary artery disease treated with rimonabant somewhat disappointing,13 the hopes for rimonabant ultimately may be realized if the drug is shown to have a favorable effect on mortality and cardiovascular events, which remains to be seen in ongoing/future clinical trials.Future trials should also address the safety concerns related to the increased incidence of psychiatric side effects of rimonabant (this was partially addressed by STRADIVARIUS13 and Van Gaal et al12 recently), largely responsible for the FDA Advisory Panel's rejection of the approval of the drug for obesity in the United States in 2007. This issue appears to be particularly important in light of the recent announcement of Merck about the discontinuation of the clinical development of their lead CB1 antagonist taranabant for obesity, because of the increased incidence of dose-dependent CNS side effects (http://www.merck.com/newsroom/press_releases/research_and_development/2008_1002.html), and similar recent concerns expressed by European Medicines Agency regarding rimonabant (http://www.emea.europa.eu/humandocs/PDFs/EPAR/acomplia/32982607en.pdf, http://www.sanofi-aventis.us/live/us/medias/7706E488-788C-412C-9591-73CDC18C468F.pdf).In this issue of Arteriosclerosis, Thrombosis, and Vascular Biology, Dol-Gleizes et al14 present interesting results of a study of the effects of rimonabant on atherosclerosis progression using LDLR−/− mice fed a Western-type diet for 3 months. They found that rimonabant (50 mg/kg/d in the diet p.o.) significantly reduced food intake, weight gain, serum total cholesterol, and almost completely abolished the atherosclerotic lesion development in the aorta and aortic sinus of LDLR−/− mice fed a Western-type diet for 3 months. Rimonabant also reduced plasma levels of the proinflammatory cytokines/chemokines such as monocyte chemotactic protein-1 (MCP-1), IL-12, and vascular cell adhesion molecule-1,14 all implicated in the development/progression of atherosclerosis. Importantly, pair-fed animals had reduced weight gain, but developed atherosclerotic lesions which were as large as those of untreated animals, demonstrating that the surprisingly strong antiatherosclerotic effect of rimonabant was not related to inhibition of food intake.14 This effect could be explained by either the increase of HDL/LDL cholesterol ratio or the decrease in inflammation, or both. However, when rimonabant was administered at a lower dose (30 mg/kg/d), which surprisingly did not affect serum total cholesterol levels, it was still able to attenuate the atherosclerosis development, implicating an antiinflammatory effect of the compound. To further clarify the mechanism of action of rimonabant, the authors determined the effect of rimonabant on inflammatory gene expression in macrophages, the major cell types involved in atherosclerosis lesion progression.15,16 They found that rimonabant decreased bacterial endotoxin (LPS)- and IL-1β–induced proinflammatory gene expression in mouse peritoneal macrophages in vitro as well as thioglycollate-induced recruitment of macrophages in vivo. Interestingly, the antiinflammatory effects of the compound on proinflammatory gene expression were also preserved in CB1 knockout mouse macrophages stimulated with LPS, indicating that these antiinflammatory effects are not related to the CB1 blockade.14 Indeed, rimonabant appears to exert potent antiinflammatory and cytoprotective effects in multiple preclinical disease models.17–20 For example, chronic rimonabant treatment increases the reduced plasma level of the antiinflammatory hormone adiponectin, reduces the elevated plasma/serum levels of TNF-α,17 reduces RANTES (REGULATED ON ACTIVATION, NORMAL T cell Expressed, and Secreted) and MCP-119 in obese Zucker fa/fa rats, and decreases NF-kappaB activation and consequent iNOS expression in mitogen-stimulated human peripheral blood mononuclear cells.18 In the context of atherosclerosis, the above mentioned effect of rimonabant on plasma TNF-α, serum MCP-1, NF-kappaB activation in stimulated human peripheral blood mononuclear cells, and on LPS-stimulated macrophage inflammatory responses, are particularly important, because proinflammatory cytokines such as TNF-α and bacterial endotoxin(s) are crucial mediators in the development of atherosclerosis.15,16 They promote NF-κB–dependent upregulation of chemokines (eg, MCP-1) and adhesion molecules (eg, intercellular adhesion molecule-1, vascular cell adhesion molecule-1) in endothelial cells, resulting in recruitment and increased adhesion of monocytes to the activated endothelium followed by transendothelial migration and activation.15,16 Monocytes in concert with the activated endothelium also release a variety of factors that promote smooth muscle cell proliferation and migration from the media into the intima and consequent synthesis and deposition of extracellular matrix.15,16Collectively, considering the beneficial effect of rimonabant on serum lipid parameters observed both in obese patients and in animal models, the decreased atherosclerotic lesion development by higher dose of rimonabant is not surprising. However, the demonstration that rimonabant even at a lower dose, which is not affecting serum total cholesterol levels, is able to reduce atherosclerosis development (presumably by exerting antiinflammatory effects not exclusively mediated by the CB1 blockade) is the most important message of this study, which also has far reaching clinical implications. Given the increasing recognition of the importance of the complex interplay of the lipid signaling and vascular inflammatory processes associated with atherosclerosis,16,21 the dual beneficial effects of rimonabant on serum lipid parameters and inflammatory processes, and the ability to attenuate the platelet-derived growth factor–induced human coronary artery smooth muscle cell proliferation and migration,22 are particularly encouraging from the clinical point of view (even if some of these effects may not exclusively be mediated by the CB1 blockade), forecasting possible benefits in a range of cardiovascular disorders associated with chronic inflammation in patients. It would be very interesting to see in ongoing/future long-term clinical trials with rimonabant whether the favorable effects observed in preclinical models and in the above mentioned clinical reports can actually be translated into decreased mortality and cardiovascular events in patients. It would also be very interesting to see how the efficacy and safety of additional CB1 antagonists entering the clinical arena, and perhaps future peripherally active CB1 antagonists aiming to limit the CNS side effects, compares with that of rimonabant. The beneficial effects of rimonabant observed in preclinical/clinical studies with potential relevance to atherosclerosis and cardiovascular diseases/risk are summarized in the Figure. Download figureDownload PowerPointFigure. Selected beneficial effects of CB1 receptor antagonist rimonabant observed in preclinical/clinical studies with potential relevance to atherosclerosis and cardiovascular diseases/risk. Please note that some of the antiinflammatory and possibly other effects may not exclusively be mediated by the CB1 blockade.Sources of FundingThis publication was supported by Intramural Research Program of NIH.DisclosuresNone.FootnotesCorrespondence to Pál Pacher, MD, PhD, FAPS, FAHA, Section on Oxidative Stress Tissue Injury, Laboratory of Physiologic Studies/NIAAA, National Institutes of Health, 5625 Fishers Lane, MSC-9413, Bethesda, MD 20892-9413. E-mail [email protected] References 1 Pacher P, Batkai S, Kunos G. The endocannabinoid system as an emerging target of pharmacotherapy. Pharmacol Rev. 2006; 58: 389–462.CrossrefMedlineGoogle Scholar2 Di Marzo V. Targeting the endocannabinoid system: to enhance or reduce? Nat Rev Drug Discov. 2008; 7: 438–455.CrossrefMedlineGoogle Scholar3 Pacher P, Mukhopadhyay P, Mohanraj R, Godlewski G, Batkai S, Kunos G. Modulation of the endocannabinoid system in cardiovascular disease: therapeutic potential and limitations. Hypertension. 2008; 52: 601–607.LinkGoogle Scholar4 Steffens S, Veillard NR, Arnaud C, Pelli G, Burger F, Staub C, Karsak M, Zimmer A, Frossard JL, Mach F. Low dose oral cannabinoid therapy reduces progression of atherosclerosis in mice. Nature. 2005; 434: 782–786.CrossrefMedlineGoogle Scholar5 Rajesh M, Mukhopadhyay P, Batkai S, Hasko G, Liaudet L, Huffman JW, Csiszar A, Ungvari Z, Mackie K, Chatterjee S, Pacher P. 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: H2210–H2218.CrossrefMedlineGoogle Scholar6 Despres JP, Golay A, Sjostrom L. Effects of rimonabant on metabolic risk factors in overweight patients with dyslipidemia. N Engl J Med. 2005; 353: 2121–2134.CrossrefMedlineGoogle Scholar7 Van Gaal LF, Rissanen AM, Scheen AJ, Ziegler O, Rossner S. Effects of the cannabinoid-1 receptor blocker rimonabant on weight reduction and cardiovascular risk factors in overweight patients: 1-year experience from the RIO-Europe study. Lancet. 2005; 365: 1389–1397.CrossrefMedlineGoogle Scholar8 Scheen AJ, Finer N, Hollander P, Jensen MD, Van Gaal LF. Efficacy and tolerability of rimonabant in overweight or obese patients with type 2 diabetes: a randomised controlled study. Lancet. 2006; 368: 1660–1672.CrossrefMedlineGoogle Scholar9 Pi-Sunyer FX, Aronne LJ, Heshmati HM, Devin J, Rosenstock J. Effect of rimonabant, a cannabinoid-1 receptor blocker, on weight and cardiometabolic risk factors in overweight or obese patients: RIO-North America: a randomized controlled trial. JAMA. 2006; 295: 761–775.CrossrefMedlineGoogle Scholar10 Van Gaal L, Pi-Sunyer X, Despres JP, McCarthy C, Scheen A. Efficacy and safety of rimonabant for improvement of multiple cardiometabolic risk factors in overweight/obese patients: pooled 1-year data from the Rimonabant in Obesity (RIO) program. Diabetes Care. 2008; 31: S229–S240.CrossrefMedlineGoogle Scholar11 Rosenstock J, Hollander P, Chevalier S, Iranmanesh A. SERENADE: The Study Evaluating Rimonabant Efficacy in Drug-Naive Diabetic Patients: Effects of monotherapy with rimonabant, the first selective CB1 receptor antagonist, on glycemic control, body weight, and lipid profile in drug-naive type 2 diabetes. Diabetes Care. 2008; 31: 2169–2176.CrossrefMedlineGoogle Scholar12 Van Gaal LF, Scheen AJ, Rissanen AM, Rossner S, Hanotin C, Ziegler O. 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: 1761–1771.CrossrefMedlineGoogle Scholar13 Nissen SE, Nicholls SJ, Wolski K, Rodes-Cabau J, Cannon CP, Deanfield JE, Despres JP, Kastelein JJ, Steinhubl SR, Kapadia S, Yasin M, Ruzyllo W, Gaudin C, Job B, Hu B, Bhatt DL, Lincoff AM, Tuzcu EM. Effect of rimonabant on progression of atherosclerosis in patients with abdominal obesity and coronary artery disease: the STRADIVARIUS randomized controlled trial. JAMA. 2008; 299: 1547–1560.CrossrefMedlineGoogle Scholar14 Dol-Gleizes F, Paumelle R, Visentin V, Mares AM, Desitter P, Hennuyer N, Gilde A, Staels B, Schaeffer P, Bono F. Rimonabant, a selective cannabinoid CB1 receptor antagonist, inhibits atherosclerosis in LDL receptor-deficient mice. Arterioscler Thromb Vasc Biol. 2009; 29: 12–18.LinkGoogle Scholar15 Osterud B, Bjorklid E. Role of monocytes in atherogenesis. Physiol Rev. 2003; 83: 1069–1112.CrossrefMedlineGoogle Scholar16 Tedgui A, Mallat Z. Cytokines in atherosclerosis: pathogenic and regulatory pathways. Physiol Rev. 2006; 86: 515–581.CrossrefMedlineGoogle Scholar17 Gary-Bobo M, Elachouri G, Gallas JF, Janiak P, Marini P, Ravinet-Trillou C, Chabbert M, Cruccioli N, Pfersdorff C, Roque C, Arnone M, Croci T, Soubrie P, Oury-Donat F, Maffrand JP, Scatton B, Lacheretz F, Le Fur G, Herbert JM, Bensaid M. Rimonabant reduces obesity-associated hepatic steatosis and features of metabolic syndrome in obese Zucker fa/fa rats. Hepatology. 2007; 46: 122–129.CrossrefMedlineGoogle Scholar18 Malfitano AM, Laezza C, Pisanti S, Gazzerro P, Bifulco M. Rimonabant (SR141716) exerts anti-proliferative and immunomodulatory effects in human peripheral blood mononuclear cells. Br J Pharmacol. 2008; 153: 1003–1010.CrossrefMedlineGoogle Scholar19 Schafer A, Pfrang J, Neumuller J, Fiedler S, Ertl G, Bauersachs J. The cannabinoid receptor-1 antagonist rimonabant inhibits platelet activation and reduces pro-inflammatory chemokines and leukocytes in Zucker rats. Br J Pharmacol. In press. doi: 10.1016/j.bbrc.2008.10.159.Google Scholar20 Mukhopadhyay P, Batkai S, Rajesh M, Czifra N, Harvey-White J, Hasko G, Zsengeller Z, Gerard NP, Liaudet L, Kunos G, Pacher P. Pharmacological inhibition of CB1 cannabinoid receptor protects against doxorubicin-induced cardiotoxicity. J Am Coll Cardiol. 2007; 50: 528–536.CrossrefMedlineGoogle Scholar21 Weber C, Zernecke A, Libby P. The multifaceted contributions of leukocyte subsets to atherosclerosis: lessons from mouse models. Nat Rev Immunol. 2008; 8: 802–815.CrossrefMedlineGoogle Scholar22 Rajesh M, Mukhopadhyay P, Hasko G, Pacher P. Cannabinoid CB1 receptor inhibition decreases vascular smooth muscle migration and proliferation. Biochem Biophys Res Commun. In press.Google Scholar Previous Back to top Next FiguresReferencesRelatedDetailsCited By Ghasemi-Gojani E, Kovalchuk I and Kovalchuk O (2022) Cannabinoids and terpenes for diabetes mellitus and its complications: from mechanisms to new therapies, Trends in Endocrinology & Metabolism, 10.1016/j.tem.2022.08.003, 33:12, (828-849), Online publication date: 1-Dec-2022. Mazdai L, Fabbri M, Tirri M, Corli G, Arfè R, Marchetti B, Bilel S, Bergamin E, Gaudio R, Rubini M, De-Giorgio F and Marti M (2022) Epigenetic Studies for Evaluation of NPS Toxicity: Focus on Synthetic Cannabinoids and Cathinones, Biomedicines, 10.3390/biomedicines10061398, 10:6, (1398) Ceballos-Gutiérrez A, Rodríguez-Hernández A, Álvarez-Valadez M, Limón-Miranda S, Andrade F, Figueroa-Gutiérrez A, Díaz-Reval I, Apolinar-Iribe A, Castro-Sánchez L, Alamilla J, Sánchez-Pastor E and Virgen-Ortiz A (2021) ZnO Nanoparticles Induce Dyslipidemia and Atherosclerotic Lesions Leading to Changes in Vascular Contractility and Cannabinoid Receptors Expression as Well as Increased Blood Pressure, Nanomaterials, 10.3390/nano11092319, 11:9, (2319) Wang Y, Pan W, Wang Y and Yin Y (2020) The GPR55 antagonist CID16020046 protects against ox-LDL-induced inflammation in human aortic endothelial cells (HAECs), Archives of Biochemistry and Biophysics, 10.1016/j.abb.2020.108254, 681, (108254), Online publication date: 1-Mar-2020. Pacher P, Steffens S, Haskó G, Schindler T and Kunos G (2017) Cardiovascular effects of marijuana and synthetic cannabinoids: the good, the bad, and the ugly, Nature Reviews Cardiology, 10.1038/nrcardio.2017.130, 15:3, (151-166), Online publication date: 1-Mar-2018. Gertsch J (2017) Cannabimimetic phytochemicals in the diet - an evolutionary link to food selection and metabolic stress adaptation?, British Journal of Pharmacology, 10.1111/bph.13676, 174:11, (1464-1483), Online publication date: 1-Jun-2017. Dobovišek L, Hojnik M and Ferk P (2016)(2016) Overlapping molecular pathways between cannabinoid receptors type 1 and 2 and estrogens/androgens on the periphery and their involvement in the pathogenesis of common diseases (Review), International Journal of Molecular Medicine, 10.3892/ijmm.2016.2779, 38:6, (1642-1651), Online publication date: 1-Dec-2016. Lanuti M, Talamonti E, Maccarrone M, Chiurchiù V and Cignarella A (2015) Activation of GPR55 Receptors Exacerbates oxLDL-Induced Lipid Accumulation and Inflammatory Responses, while Reducing Cholesterol Efflux from Human Macrophages, PLOS ONE, 10.1371/journal.pone.0126839, 10:5, (e0126839) Alshaarawy O and Anthony J (2015) Cannabis smoking and serum C-reactive protein: A quantile regressions approach based on NHANES 2005–2010, Drug and Alcohol Dependence, 10.1016/j.drugalcdep.2014.11.017, 147, (203-207), Online publication date: 1-Feb-2015. Chiurchiù V, Lanuti M, Catanzaro G, Fezza F, Rapino C and Maccarrone M (2014) Detailed characterization of the endocannabinoid system in human macrophages and foam cells, and anti-inflammatory role of type-2 cannabinoid receptor, Atherosclerosis, 10.1016/j.atherosclerosis.2013.12.042, 233:1, (55-63), Online publication date: 1-Mar-2014. Molica F, Burger F, Thomas A, Staub C, Tailleux A, Staels B, Pelli G, Zimmer A, Cravatt B, Matter C, Pacher P and Steffens S (2013) Endogenous cannabinoid receptor CB1 activation promotes vascular smooth-muscle cell proliferation and neointima formation, Journal of Lipid Research, 10.1194/jlr.M035147, 54:5, (1360-1368), Online publication date: 1-May-2013. Cappellano G, Uberti F, Caimmi P, Pietronave S, Mary D, Dianzani C, Micalizzi E, Melensi M, Boldorini R, Nicosia G, Crosio E, Chiocchetti A, Aina F, Prat M, Dianzani U, Vacca G, Ariatti C and Grossini E (2013) Different Expression and Function of the Endocannabinoid System in Human Epicardial Adipose Tissue in Relation to Heart Disease, Canadian Journal of Cardiology, 10.1016/j.cjca.2012.06.003, 29:4, (499-509), Online publication date: 1-Apr-2013. Lenglet S, Thomas A, Soehnlein O, Montecucco F, Burger F, Pelli G, Galan K, Cravatt B, Staub C and Steffens S (2012) Fatty Acid Amide Hydrolase Deficiency Enhances Intraplaque Neutrophil Recruitment in Atherosclerotic Mice, Arteriosclerosis, Thrombosis, and Vascular Biology, 33:2, (215-223), Online publication date: 1-Feb-2013. Steffens S and Pacher P (2012) Targeting cannabinoid receptor CB2 in cardiovascular disorders: promises and controversies, British Journal of Pharmacology, 10.1111/j.1476-5381.2012.02042.x, 167:2, (313-323), Online publication date: 1-Sep-2012. Feuerecker M, Hauer D, Gresset T, Lassas S, Kaufmann I, Vogeser M, Briegel J, Hornuss C, Choukèr A and Schelling G (2012) Effect of an Acute Consumption of a Moderate Amount of Ethanol on Plasma Endocannabinoid Levels in Humans, Alcohol and Alcoholism, 10.1093/alcalc/agr162, 47:3, (226-232), Online publication date: 1-May-2012. Mukhopadhyay P, Rajesh M, Horváth B, Bátkai S, Park O, Tanchian G, Gao R, Patel V, Wink D, Liaudet L, Haskó G, Mechoulam R and Pacher P (2011) Cannabidiol protects against hepatic ischemia/reperfusion injury by attenuating inflammatory signaling and response, oxidative/nitrative stress, and cell death, Free Radical Biology and Medicine, 10.1016/j.freeradbiomed.2011.02.021, 50:10, (1368-1381), Online publication date: 1-May-2011. Mukhopadhyay P, Horváth B, Rajesh M, Matsumoto S, Saito K, Bátkai S, Patel V, Tanchian G, Gao R, Cravatt B, Haskó G and Pacher P (2011) Fatty acid amide hydrolase is a key regulator of endocannabinoid-induced myocardial tissue injury, Free Radical Biology and Medicine, 10.1016/j.freeradbiomed.2010.11.002, 50:1, (179-195), Online publication date: 1-Jan-2011. Zhao Y, Liu Y, Zhang W, Xue J, Wu Y, Xu W, Liang X, Chen T, Kishimoto C and Yuan Z (2010) WIN55212-2 ameliorates atherosclerosis associated with suppression of pro-inflammatory responses in ApoE-knockout mice, European Journal of Pharmacology, 10.1016/j.ejphar.2010.09.027, 649:1-3, (285-292), Online publication date: 1-Dec-2010. Liu W, Jin H, Park J, Baek H and Park T (2010) Effect of rimonabant, the cannabinoid CB1 receptor antagonist, on peripheral nerve in streptozotocin-induced diabetic rat, European Journal of Pharmacology, 10.1016/j.ejphar.2010.04.004, 637:1-3, (70-76), Online publication date: 1-Jul-2010. Mukhopadhyay P, Pan H, Rajesh M, Bátkai S, Patel V, Harvey-White J, Mukhopadhyay B, Haskó G, Gao B, Mackie K and Pacher P (2010) CB 1 cannabinoid receptors promote oxidative/nitrosative stress, inflammation and cell death in a murine nephropathy model , British Journal of Pharmacology, 10.1111/j.1476-5381.2010.00769.x, 160:3, (657-668), Online publication date: 1-Jun-2010. Rajesh M, Mukhopadhyay P, Haskó G, Liaudet L, Mackie K and Pacher P (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, British Journal of Pharmacology, 10.1111/j.1476-5381.2010.00712.x, 160:3, (688-700), Online publication date: 1-Jun-2010. Zhao Y, Yuan Z, Liu Y, Xue J, Tian Y, Liu W, Zhang W, Shen Y, Xu W, Liang X and Chen T (2010) Activation of Cannabinoid CB2 Receptor Ameliorates Atherosclerosis Associated With Suppression of Adhesion Molecules, Journal of Cardiovascular Pharmacology, 10.1097/FJC.0b013e3181d2644d, 55:3, (292-298), Online publication date: 1-Mar-2010. Pacher P and Steffens S (2009) The emerging role of the endocannabinoid system in cardiovascular disease, Seminars in Immunopathology, 10.1007/s00281-009-0145-8, 31:1, (63-77), Online publication date: 1-Jun-2009. Taskinen M (2009) ADAGIO-Lipids Gives Promises but Faces the Setbacks, Arteriosclerosis, Thrombosis, and Vascular Biology, 29:3, (339-340), Online publication date: 1-Mar-2009. January 2009Vol 29, Issue 1 Advertisement Article InformationMetrics https://doi.org/10.1161/ATVBAHA.108.178129PMID: 19092136 Originally publishedJanuary 1, 2009 Keywordsatherosclerosismyocardial infarctionmetabolic syndromediabetescardiovascularendocannabinoidsPDF download Advertisement
Referência(s)