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Luckhoff HK, Smit AM, Phahladira L, Kilian S, Emsley R, Asmal L. Childhood trauma associations with changes in body mass index over 12 months of treatment in first-episode schizophrenia spectrum disorders. Schizophr Res 2025; 281:52-59. [PMID: 40318310 DOI: 10.1016/j.schres.2025.04.031] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 10/22/2024] [Revised: 03/27/2025] [Accepted: 04/28/2025] [Indexed: 05/07/2025]
Abstract
BACKGROUND Childhood trauma (CT) is a risk factor for the development of adulthood obesity, both in the general population, and in patients with schizophrenia. AIM We examined the associations between CT exposure and visit-wise changes in body mass index (BMI) over 12 months of treatment in patents with first-episode schizophrenia spectrum disorders (FES) (n = 77) compared to matched controls (n = 55). We also examined the moderating effects of socio-demographic, clinical, and treatment-related factors on the relationships between CT exposure and weight gain in patients. METHODS CT was assessed using the Childhood Trauma Questionnaire. BMI was assessed at baseline in patients and controls and again at regular 3-month intervals in patients. Linear mixed effect models for continuous repeated measures (MMRM) were constructed to examine the effects of CT exposure on visit-wise changes in BMI over time. RESULTS Patients had a lower baseline BMI than controls, but were balanced for CT exposure. In patients, but not in controls, more severe childhood emotional abuse (EA) correlated with a higher baseline BMI. Initial MMRM indicated that higher childhood EA was associated with more pronounced weight gain over 12 months in patients. Explorative MMRM indicated that this effect was limited to cannabis non-users, and no longer significant in cannabis users. DISCUSSION Cannabis use moderated the association between childhood EA and more pronounced weight gain in FES. Future studies would do well to examine the effects of other risk and resilience factors on the relationships between CT exposure and metabolic syndrome changes in schizophrenia.
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Affiliation(s)
- H K Luckhoff
- Department of Psychiatry, Faculty of Medicine and Health Sciences, Stellenbosch University, Cape Town, South Africa.
| | - A M Smit
- Department of Psychiatry, Faculty of Medicine and Health Sciences, Stellenbosch University, Cape Town, South Africa
| | - L Phahladira
- Department of Psychiatry, Faculty of Medicine and Health Sciences, Stellenbosch University, Cape Town, South Africa
| | - S Kilian
- Department of Psychiatry, Faculty of Medicine and Health Sciences, Stellenbosch University, Cape Town, South Africa
| | - R Emsley
- Department of Psychiatry, Faculty of Medicine and Health Sciences, Stellenbosch University, Cape Town, South Africa
| | - L Asmal
- Department of Psychiatry, Faculty of Medicine and Health Sciences, Stellenbosch University, Cape Town, South Africa
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Smith GL. Weight Loss and Therapeutic Metabolic Effects of Tetrahydrocannabivarin (THCV)-Infused Mucoadhesive Strips. CANNABIS (ALBUQUERQUE, N.M.) 2025; 8:109-120. [PMID: 39968488 PMCID: PMC11831893 DOI: 10.26828/cannabis/2024/000206] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Subscribe] [Scholar Register] [Indexed: 02/20/2025]
Abstract
Objective Metabolic syndrome is due to dysregulation that starts with fat accumulation, causing inflammatory response, insulin resistance, dyslipidemia, hypertension, and fatty liver disease. The endocannabinoid system, via cannabinoid receptor type 1 (CB1), has been shown to be involved with energy homeostasis and regulation of appetitive behavior via activity in the hypothalamus, limbic forebrain and amygdala and in the peripheral tissues including adipose, liver and muscle. Therefore, two phytocannabinoids, tetrahydrocannabivarin (THCV), a CB1 neutral antagonist, and cannabidiol (CBD), a negative allosteric modulator of CB1, are expected to have therapeutic metabolic benefits, including weight loss. Method A placebo-controlled study was conducted on 44 subjects (31 females and 13 males) with an average age of 51.75. The study evaluated the efficacy of two different doses of THCV and CBD (8 mg THCV/10 mg CBD in the lower dose and 16 mg THCV/20 mg CBD in the higher dose), taken once daily for 90 days via mucoadhesive oral strips, for weight loss and improvement of certain metabolic markers. Results Use of the THCV/CBD strip was associated with statistically significant weight loss, decreases in abdominal girth, systolic blood pressure, and total and LDL cholesterol. The study was limited by small sample sizes in both the high dose and placebo groups. Conclusions The 16 mg/20 mg daily dose was superior for weight loss compared to the 8 mg/10 mg daily dose; both sets of results differed from placebo in a way that was statistically significant. The results of this study were congruent with the prior unpublished studies of a hemp extract containing significant percentages of THCV, CBDV and CBD.
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Chandy M, Jimenez-Tellez N, Wu JC. The relationship between cannabis and cardiovascular disease: clearing the haze. Nat Rev Cardiol 2025:10.1038/s41569-025-01121-6. [PMID: 39849111 DOI: 10.1038/s41569-025-01121-6] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Accepted: 01/08/2025] [Indexed: 01/25/2025]
Abstract
Cannabis has been consumed for centuries, but global regulatory changes over the past three decades have increased the availability and consumption of cannabis. Cannabinoids are touted to have therapeutic potential for many diseases and could be a replacement for opioids for analgesia and sedation. However, cannabinoids can cause substantial adverse cardiovascular events that would mitigate any potential benefit. The endocannabinoid system regulates mood, satiety and memory, and modulates the cardiovascular system. The link between cannabinoids and cardiovascular disease, which used to be limited to evidence from preclinical studies, case reports and case series, is now evident in epidemiological studies. Cannabinoids adversely affect the cardiovascular system, causing myocardial infarction, cerebrovascular accidents, arrhythmia and heart failure. The effects of novel cannabinoids are unknown, and synthetic cannabinoids have the potential to cause even more substantial harm than traditional cannabinoids. Therefore, with the increasing availability and use of cannabis, the acute and chronic effects of this drug are becoming apparent.
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Affiliation(s)
- Mark Chandy
- Stanford Cardiovascular Institute, Stanford, CA, USA.
- Department of Medicine, Division of Cardiology, Stanford University School of Medicine, Stanford, CA, USA.
- Department of Medicine, Western University, London, Ontario, Canada.
| | - Nerea Jimenez-Tellez
- Stanford Cardiovascular Institute, Stanford, CA, USA
- Department of Medicine, Division of Cardiology, Stanford University School of Medicine, Stanford, CA, USA
| | - Joseph C Wu
- Stanford Cardiovascular Institute, Stanford, CA, USA.
- Department of Medicine, Division of Cardiology, Stanford University School of Medicine, Stanford, CA, USA.
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Wainwright CL, Walsh SK. Pharmacology of Non-Psychoactive Phytocannabinoids and Their Potential for Treatment of Cardiometabolic Disease. Handb Exp Pharmacol 2025; 287:61-93. [PMID: 39235486 DOI: 10.1007/164_2024_731] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 09/06/2024]
Abstract
The use of Cannabis sativa by humans dates back to the third millennium BC, and it has been utilized in many forms for multiple purposes, including production of fibre and rope, as food and medicine, and (perhaps most notably) for its psychoactive properties for recreational use. The discovery of Δ9-tetrahydrocannabinol (Δ9-THC) as the main psychoactive phytocannabinoid contained in cannabis by Gaoni and Mechoulam in 1964 (J Am Chem Soc 86, 1646-1647), was the first major step in cannabis research; since then the identification of the chemicals (phytocannabinoids) present in cannabis, the classification of the pharmacological targets of these compounds and the discovery that the body has its own endocannabinoid system (ECS) have highlighted the potential value of cannabis-derived compounds in the treatment of many diseases, such as neurological disorders and cancers. Although the use of Δ9-THC as a therapeutic agent is constrained by its psychoactive properties, there is growing evidence that non-psychoactive phytocannabinoids, derived from both Cannabis sativa and other plant species, as well as non-cannabinoid compounds found in Cannabis sativa, have real potential as therapeutics. This chapter will focus on the possibilities for using these compounds in the prevention and treatment of cardiovascular disease and related metabolic disturbances.
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Affiliation(s)
- Cherry L Wainwright
- Centre for Cardiometabolic Health Research, School of Pharmacy & Life Sciences, Robert Gordon University, Aberdeen, Scotland, UK.
| | - Sarah K Walsh
- Centre for Cardiometabolic Health Research, School of Pharmacy & Life Sciences, Robert Gordon University, Aberdeen, Scotland, UK
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Blessing E, Teichmann E, Hinz B. Anandamide Inhibits Vascular Smooth Muscle Migration, Endothelial Adhesion Protein Expression and Monocyte Adhesion of Human Coronary Artery Cells. Cells 2024; 13:2108. [PMID: 39768198 PMCID: PMC11727187 DOI: 10.3390/cells13242108] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/23/2024] [Revised: 11/29/2024] [Accepted: 12/03/2024] [Indexed: 01/16/2025] Open
Abstract
Endocannabinoids have been shown to play a complex role in the pathophysiology of a number of cardiovascular disorders. In the present study, the effects of the two major endocannabinoids anandamide (AEA) and 2-arachidonoylglycerol (2-AG) were investigated in human coronary artery smooth muscle cells (HCASMC) and human coronary artery endothelial cells (HCAEC) with regard to potential atheroprotective and anti-inflammatory effects. In HCASMC, AEA showed an inhibitory effect on platelet-derived growth factor-induced migration, but not proliferation, independent of major cannabinoid-activatable receptors (CB1, CB2, TRPV1), while 2-AG left both responses unaffected. In HCAEC, AEA at concentrations of 6 and 10 µM significantly inhibited the interleukin (IL)-1β- and lipopolysaccharide (LPS)-stimulated expression of vascular cell adhesion molecule-1 (VCAM-1) and LPS-induced intercellular adhesion molecule-1 (ICAM-1), again independently of the abovementioned receptors. Corresponding effects were observed to a lesser extent in the presence of 2-AG, in most cases not significantly. The detection of activated phosphoproteins as well as experiments with inhibitors of corresponding signaling pathways suggest that AEA interferes with IL-1β-induced VCAM-1 expression via inhibition of protein kinase B/Akt and Src kinase activation and attenuates LPS-induced VCAM-1 and ICAM-1 expression via inhibition of signal transducer and activator of transcription 3 (STAT3) phosphorylation. As expected, AEA also led to a significant inhibition of monocyte adhesion to IL-1β- and LPS-stimulated HCAEC, with siRNA experiments confirming the functional role of VCAM-1 and ICAM-1 in this assay. 2-AG showed a comparatively weaker but, in the case of LPS stimulation, still significant inhibition of adhesion. In summary, the results emphasize the potential of AEA as a protective regulator of atherosclerotic and inflammation-related changes in HCASMC and HCAEC and encourage further corresponding preclinical studies with this endocannabinoid.
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Affiliation(s)
| | | | - Burkhard Hinz
- Institute of Pharmacology and Toxicology, Rostock University Medical Center, Schillingallee 70, 18057 Rostock, Germany; (E.B.)
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Guo Y, Wei X, Pei J, Yang H, Zheng XL. Dissecting the role of cannabinoids in vascular health and disease. J Cell Physiol 2024; 239:e31373. [PMID: 38988064 DOI: 10.1002/jcp.31373] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/29/2024] [Revised: 06/04/2024] [Accepted: 06/27/2024] [Indexed: 07/12/2024]
Abstract
Cannabis, often recognized as the most widely used illegal psychoactive substance globally, has seen a shift in its legal status in several countries and regions for both recreational and medicinal uses. This change has brought to light new evidence linking cannabis consumption to various vascular conditions. Specifically, there is an association between cannabis use and atherosclerosis, along with conditions such as arteritis, reversible vasospasm, and incidents of aortic aneurysm or dissection. Recent research has started to reveal the mechanisms connecting cannabinoid compounds to atherosclerosis development. It is well known that the primary biological roles of cannabinoids operate through the activation of cannabinoid receptor types 1 and 2. Manipulation of the endocannabinoid system, either genetically or pharmacologically, is emerging as a promising approach to address metabolic dysfunctions related to obesity. Additionally, numerous studies have demonstrated the vasorelaxant properties and potential atheroprotective benefits of cannabinoids. In preclinical trials, cannabidiol is being explored as a treatment option for monocrotaline-induced pulmonary arterial hypertension. Although existing literature suggests a direct role of cannabinoids in the pathogenesis of atherosclerosis, the correlation between cannabinoids and other vascular diseases was only reported in some case series or observational studies, and its role and precise mechanisms remain unclear. Therefore, it is necessary to summarize and update previously published studies. This review article aims to summarize the latest clinical and experimental research findings on the relationship between cannabis use and vascular diseases. It also seeks to shed light on the potential mechanisms underlying these associations, offering a comprehensive view of current knowledge in this evolving field of study.
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Affiliation(s)
- Yanan Guo
- Department of Cardiology, The First Affiliated Hospital of Zhengzhou University, Zhengzhou, China
- Department of Biochemistry and Molecular Biology, Libin Cardiovascular Institute of Alberta, Cumming School of Medicine, University of Calgary, Calgary, Alberta, Canada
- Department of Physiology and Pharmacology, Libin Cardiovascular Institute of Alberta, Cumming School of Medicine, University of Calgary, Calgary, Alberta, Canada
| | - Xiaoyun Wei
- Department of Cardiology, The Fifth School of Clinical Medicine of Henan University of Traditional Chinese Medicine, Zhengzhou, China
| | - Junyu Pei
- Department of Biochemistry and Molecular Biology, Libin Cardiovascular Institute of Alberta, Cumming School of Medicine, University of Calgary, Calgary, Alberta, Canada
- Department of Physiology and Pharmacology, Libin Cardiovascular Institute of Alberta, Cumming School of Medicine, University of Calgary, Calgary, Alberta, Canada
| | - Haibo Yang
- Department of Cardiology, The First Affiliated Hospital of Zhengzhou University, Zhengzhou, China
| | - Xi-Long Zheng
- Department of Biochemistry and Molecular Biology, Libin Cardiovascular Institute of Alberta, Cumming School of Medicine, University of Calgary, Calgary, Alberta, Canada
- Department of Physiology and Pharmacology, Libin Cardiovascular Institute of Alberta, Cumming School of Medicine, University of Calgary, Calgary, Alberta, Canada
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Wang Y, Li G, Chen B, Shakir G, Volz M, van der Vorst EPC, Maas SL, Geiger M, Jethwa C, Bartelt A, Li Z, Wettich J, Sachs N, Maegdefessel L, Nazari Jahantigh M, Hristov M, Lacy M, Lutz B, Weber C, Herzig S, Guillamat Prats R, Steffens S. Myeloid cannabinoid CB1 receptor deletion confers atheroprotection in male mice by reducing macrophage proliferation in a sex-dependent manner. Cardiovasc Res 2024; 120:1411-1426. [PMID: 38838211 PMCID: PMC11481387 DOI: 10.1093/cvr/cvae125] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 01/26/2024] [Revised: 03/21/2024] [Accepted: 05/01/2024] [Indexed: 06/07/2024] Open
Abstract
AIMS Although the cannabinoid CB1 receptor has been implicated in atherosclerosis, its cell-specific effects in this disease are not well understood. To address this, we generated a transgenic mouse model to study the role of myeloid CB1 signalling in atherosclerosis. METHODS AND RESULTS Here, we report that male mice with myeloid-specific Cnr1 deficiency on atherogenic background developed smaller lesions and necrotic cores than controls, while only minor genotype differences were observed in females. Male Cnr1-deficient mice showed reduced arterial monocyte recruitment and macrophage proliferation with less inflammatory phenotype. The sex-specific differences in proliferation were dependent on oestrogen receptor (ER)α-oestradiol signalling. Kinase activity profiling identified a CB1-dependent regulation of p53 and cyclin-dependent kinases. Transcriptomic profiling further revealed chromatin modifications, mRNA processing, and mitochondrial respiration among the key processes affected by CB1 signalling, which was supported by metabolic flux assays. Chronic administration of the peripherally restricted CB1 antagonist JD5037 inhibited plaque progression and macrophage proliferation, but only in male mice. Finally, CNR1 expression was detectable in human carotid endarterectomy plaques and inversely correlated with proliferation, oxidative metabolism, and inflammatory markers, suggesting a possible implication of CB1-dependent regulation in human pathophysiology. CONCLUSION Impaired macrophage CB1 signalling is atheroprotective by limiting their arterial recruitment, proliferation, and inflammatory reprogramming in male mice. The importance of macrophage CB1 signalling appears to be sex-dependent.
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Affiliation(s)
- Yong Wang
- Institute for Cardiovascular Prevention, Ludwig-Maximilians-Universität Munich, Pettenkoferstr. 9, 80336 Munich, Germany
| | - Guo Li
- Institute for Cardiovascular Prevention, Ludwig-Maximilians-Universität Munich, Pettenkoferstr. 9, 80336 Munich, Germany
| | - Bingni Chen
- Institute for Cardiovascular Prevention, Ludwig-Maximilians-Universität Munich, Pettenkoferstr. 9, 80336 Munich, Germany
| | - George Shakir
- Institute for Cardiovascular Prevention, Ludwig-Maximilians-Universität Munich, Pettenkoferstr. 9, 80336 Munich, Germany
| | - Mario Volz
- Institute for Cardiovascular Prevention, Ludwig-Maximilians-Universität Munich, Pettenkoferstr. 9, 80336 Munich, Germany
| | - Emiel P C van der Vorst
- Institute for Cardiovascular Prevention, Ludwig-Maximilians-Universität Munich, Pettenkoferstr. 9, 80336 Munich, Germany
- Institute for Molecular Cardiovascular Research (IMCAR), Aachen-Maastricht Institute for CardioRenal Disease (AMICARE) and Interdisciplinary Center for Clinical Research (IZKF), RWTH Aachen University, Aachen, Germany
| | - Sanne L Maas
- Institute for Molecular Cardiovascular Research (IMCAR), Aachen-Maastricht Institute for CardioRenal Disease (AMICARE) and Interdisciplinary Center for Clinical Research (IZKF), RWTH Aachen University, Aachen, Germany
| | - Martina Geiger
- Institute for Cardiovascular Prevention, Ludwig-Maximilians-Universität Munich, Pettenkoferstr. 9, 80336 Munich, Germany
| | - Carolin Jethwa
- Institute for Cardiovascular Prevention, Ludwig-Maximilians-Universität Munich, Pettenkoferstr. 9, 80336 Munich, Germany
| | - Alexander Bartelt
- Institute for Cardiovascular Prevention, Ludwig-Maximilians-Universität Munich, Pettenkoferstr. 9, 80336 Munich, Germany
- DZHK (German Center for Cardiovasular Research), partner site Munich Heart Alliance, Pettenkoferstr. 9, 80336 Munich, Germany
- Institute for Diabetes and Cancer, Helmholtz Zentrum Munich, Neuherberg, Germany
- Department of Molecular Metabolism & Sabri Ülker Center for Metabolic Research, Harvard T.H. Chan School of Public Health, Boston, USA
| | - Zhaolong Li
- Department of Vascular and Endovascular Surgery, Klinikum rechts der Isar—Technical University Munich (TUM), Munich, Germany
| | - Justus Wettich
- Department of Vascular and Endovascular Surgery, Klinikum rechts der Isar—Technical University Munich (TUM), Munich, Germany
| | - Nadja Sachs
- Department of Vascular and Endovascular Surgery, Klinikum rechts der Isar—Technical University Munich (TUM), Munich, Germany
| | - Lars Maegdefessel
- DZHK (German Center for Cardiovasular Research), partner site Munich Heart Alliance, Pettenkoferstr. 9, 80336 Munich, Germany
- Department of Vascular and Endovascular Surgery, Klinikum rechts der Isar—Technical University Munich (TUM), Munich, Germany
| | - Maliheh Nazari Jahantigh
- Institute for Cardiovascular Prevention, Ludwig-Maximilians-Universität Munich, Pettenkoferstr. 9, 80336 Munich, Germany
| | - Michael Hristov
- Institute for Cardiovascular Prevention, Ludwig-Maximilians-Universität Munich, Pettenkoferstr. 9, 80336 Munich, Germany
| | - Michael Lacy
- Institute for Cardiovascular Prevention, Ludwig-Maximilians-Universität Munich, Pettenkoferstr. 9, 80336 Munich, Germany
| | - Beat Lutz
- Institute of Physiological Chemistry, University Medical Center, Mainz, Germany
| | - Christian Weber
- Institute for Cardiovascular Prevention, Ludwig-Maximilians-Universität Munich, Pettenkoferstr. 9, 80336 Munich, Germany
- DZHK (German Center for Cardiovasular Research), partner site Munich Heart Alliance, Pettenkoferstr. 9, 80336 Munich, Germany
- Department of Biochemistry, Cardiovascular Research Institute Maastricht (CARIM), Maastricht University Medical Centre, 6229 ER Maastricht, The Netherlands
- Munich Cluster for Systems Neurology (SyNergy), Feodor-Lynen-Straße 17, 81377 Munich, Germany
| | - Stephan Herzig
- DZHK (German Center for Cardiovasular Research), partner site Munich Heart Alliance, Pettenkoferstr. 9, 80336 Munich, Germany
- Institute for Diabetes and Cancer, Helmholtz Zentrum Munich, Neuherberg, Germany
- Chair Molecular Metabolic Control, TU Munich, Ismaninger Str. 22, 81675 Munich, Germany
- Joint Heidelberg-IDC Translational Diabetes Program, Heidelberg University Hospital, Heidelberg, Germany
| | - Raquel Guillamat Prats
- Institute for Cardiovascular Prevention, Ludwig-Maximilians-Universität Munich, Pettenkoferstr. 9, 80336 Munich, Germany
| | - Sabine Steffens
- Institute for Cardiovascular Prevention, Ludwig-Maximilians-Universität Munich, Pettenkoferstr. 9, 80336 Munich, Germany
- DZHK (German Center for Cardiovasular Research), partner site Munich Heart Alliance, Pettenkoferstr. 9, 80336 Munich, Germany
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Vass Z, Shenker-Horváth K, Bányai B, Vető KN, Török V, Gém JB, Nádasy GL, Kovács KB, Horváth EM, Jakus Z, Hunyady L, Szekeres M, Dörnyei G. Investigating the Role of Cannabinoid Type 1 Receptors in Vascular Function and Remodeling in a Hypercholesterolemic Mouse Model with Low-Density Lipoprotein-Cannabinoid Type 1 Receptor Double Knockout Animals. Int J Mol Sci 2024; 25:9537. [PMID: 39273484 PMCID: PMC11395437 DOI: 10.3390/ijms25179537] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/16/2024] [Revised: 08/24/2024] [Accepted: 08/26/2024] [Indexed: 09/15/2024] Open
Abstract
Hypercholesterolemia forms the background of several cardiovascular pathologies. LDL receptor-knockout (LDLR-KO) mice kept on a high-fat diet (HFD) develop high cholesterol levels and atherosclerosis (AS). Cannabinoid type 1 receptors (CB1Rs) induce vasodilation, although their role in cardiovascular pathologies is still controversial. We aimed to reveal the effects of CB1Rs on vascular function and remodeling in hypercholesterolemic AS-prone LDLR-KO mice. Experiments were performed on a newly established LDLR and CB1R double-knockout (KO) mouse model, in which KO and wild-type (WT) mice were kept on an HFD or a control diet (CD) for 5 months. The vascular functions of abdominal aorta rings were tested with wire myography. The vasorelaxation effects of acetylcholine (Ach, 1 nM-1 µM) were obtained after phenylephrine precontraction, which was repeated with inhibitors of nitric oxide synthase (NOS) and cyclooxygenase (COX), Nω-nitro-L-arginine (LNA), and indomethacin (INDO), respectively. Blood pressure was measured with the tail-cuff method. Immunostaining of endothelial NOS (eNOS) was carried out. An HFD significantly elevated the cholesterol levels in the LDLR-KO mice more than in the corresponding WT mice (mean values: 1039 ± 162 mg/dL vs. 91 ± 18 mg/dL), and they were not influenced by the presence of the CB1R gene. However, with the defect of the CB1R gene, damage to the Ach relaxation ability was moderated. The blood pressure was higher in the LDLR-KO mice compared to their WT counterparts (systolic/diastolic values: 110/84 ± 5.8/6.8 vs. 102/80 ± 3.3/2.5 mmHg), which was significantly elevated with an HFD (118/96 ± 1.9/2 vs. 100/77 ± 3.4/3.1 mmHg, p < 0.05) but attenuated in the CB1R-KO HFD mice. The expression of eNOS was depressed in the HFD WT mice compared to those on the CD, but it was augmented if CB1R was knocked out. This newly established double-knockout mouse model provides a tool for studying the involvement of CB1Rs in the development of hypercholesterolemia and atherosclerosis. Our results indicate that knocking out the CB1R gene significantly attenuates vascular damage in hypercholesterolemic mice.
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MESH Headings
- Animals
- Male
- Mice
- Acetylcholine/pharmacology
- Atherosclerosis/metabolism
- Atherosclerosis/genetics
- Atherosclerosis/pathology
- Atherosclerosis/etiology
- Diet, High-Fat/adverse effects
- Disease Models, Animal
- Hypercholesterolemia/metabolism
- Hypercholesterolemia/genetics
- Hypercholesterolemia/pathology
- Mice, Inbred C57BL
- Mice, Knockout
- Nitric Oxide Synthase Type III/metabolism
- Receptor, Cannabinoid, CB1/metabolism
- Receptor, Cannabinoid, CB1/genetics
- Receptors, LDL/genetics
- Receptors, LDL/metabolism
- Receptors, LDL/deficiency
- Vascular Remodeling/drug effects
- Vasodilation/drug effects
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Affiliation(s)
- Zsolt Vass
- Department of Morphology and Physiology, Faculty of Health Sciences, Semmelweis University, 17 Vas Street, 1088 Budapest, Hungary; (Z.V.); (K.S.-H.); (K.N.V.); (V.T.); (G.D.)
| | - Kinga Shenker-Horváth
- Department of Morphology and Physiology, Faculty of Health Sciences, Semmelweis University, 17 Vas Street, 1088 Budapest, Hungary; (Z.V.); (K.S.-H.); (K.N.V.); (V.T.); (G.D.)
- Center for Sports Nutrition Science, Hungarian University of Sports Science, 42-48 Alkotás Street, 1123 Budapest, Hungary
| | - Bálint Bányai
- Department of Physiology, Faculty of Medicine, Semmelweis University, 37-47 Tűzoltó Street, 1094 Budapest, Hungary; (B.B.); (J.B.G.); (G.L.N.); (K.B.K.); (E.M.H.); (Z.J.); (L.H.)
| | - Kinga Nóra Vető
- Department of Morphology and Physiology, Faculty of Health Sciences, Semmelweis University, 17 Vas Street, 1088 Budapest, Hungary; (Z.V.); (K.S.-H.); (K.N.V.); (V.T.); (G.D.)
| | - Viktória Török
- Department of Morphology and Physiology, Faculty of Health Sciences, Semmelweis University, 17 Vas Street, 1088 Budapest, Hungary; (Z.V.); (K.S.-H.); (K.N.V.); (V.T.); (G.D.)
| | - Janka Borbála Gém
- Department of Physiology, Faculty of Medicine, Semmelweis University, 37-47 Tűzoltó Street, 1094 Budapest, Hungary; (B.B.); (J.B.G.); (G.L.N.); (K.B.K.); (E.M.H.); (Z.J.); (L.H.)
| | - György L. Nádasy
- Department of Physiology, Faculty of Medicine, Semmelweis University, 37-47 Tűzoltó Street, 1094 Budapest, Hungary; (B.B.); (J.B.G.); (G.L.N.); (K.B.K.); (E.M.H.); (Z.J.); (L.H.)
| | - Kinga Bernadett Kovács
- Department of Physiology, Faculty of Medicine, Semmelweis University, 37-47 Tűzoltó Street, 1094 Budapest, Hungary; (B.B.); (J.B.G.); (G.L.N.); (K.B.K.); (E.M.H.); (Z.J.); (L.H.)
| | - Eszter Mária Horváth
- Department of Physiology, Faculty of Medicine, Semmelweis University, 37-47 Tűzoltó Street, 1094 Budapest, Hungary; (B.B.); (J.B.G.); (G.L.N.); (K.B.K.); (E.M.H.); (Z.J.); (L.H.)
| | - Zoltán Jakus
- Department of Physiology, Faculty of Medicine, Semmelweis University, 37-47 Tűzoltó Street, 1094 Budapest, Hungary; (B.B.); (J.B.G.); (G.L.N.); (K.B.K.); (E.M.H.); (Z.J.); (L.H.)
| | - László Hunyady
- Department of Physiology, Faculty of Medicine, Semmelweis University, 37-47 Tűzoltó Street, 1094 Budapest, Hungary; (B.B.); (J.B.G.); (G.L.N.); (K.B.K.); (E.M.H.); (Z.J.); (L.H.)
- Institute of Molecular Life Sciences, HUN-REN Research Centre for Natural Sciences, 2 Magyar Tudósok Körútja, 1117 Budapest, Hungary
| | - Mária Szekeres
- Department of Morphology and Physiology, Faculty of Health Sciences, Semmelweis University, 17 Vas Street, 1088 Budapest, Hungary; (Z.V.); (K.S.-H.); (K.N.V.); (V.T.); (G.D.)
- Department of Physiology, Faculty of Medicine, Semmelweis University, 37-47 Tűzoltó Street, 1094 Budapest, Hungary; (B.B.); (J.B.G.); (G.L.N.); (K.B.K.); (E.M.H.); (Z.J.); (L.H.)
| | - Gabriella Dörnyei
- Department of Morphology and Physiology, Faculty of Health Sciences, Semmelweis University, 17 Vas Street, 1088 Budapest, Hungary; (Z.V.); (K.S.-H.); (K.N.V.); (V.T.); (G.D.)
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9
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Kumar N, Paray NKB, Ramphul K, Verma R, Dhaliwal JS, Schroeder C, Liu L, Bawna F, Sakthivel H, Ahmed R. Unmasking the cannabis paradox: in-hospital outcomes of cannabis users admitted with acute myocardial infarction over a 20-year period in the United States. Arch Med Sci Atheroscler Dis 2024; 9:e137-e146. [PMID: 39086618 PMCID: PMC11289235 DOI: 10.5114/amsad/189731] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/26/2024] [Accepted: 06/06/2024] [Indexed: 08/02/2024] Open
Abstract
Introduction Cannabis is increasingly becoming a socially acceptable substance, with multiple countries having legalised its consumption. Epidemiological studies have demonstrated an association between cannabis use and an increased risk of developing coronary artery disease. However, there is a lack of studies about the influence of cannabis consumption on the outcomes following acute myocardial infarction (AMI). Material and methods We retrospectively analysed hospitalised patients with a primary diagnosis of AMI from the 2001 to 2020 National Inpatient Sample (NIS). Pearson's χ2 tests were applied to categorical variables, and t-tests for continuous variables. We conducted a 1:1 propensity score matching (PSM). Multivariate regression models were deployed on the PSM sample to estimate the differences in several events and all-cause mortality. Results A total of 9,930,007 AMI patients were studied, of whom 117,641 (1.2%) reported cannabis use. Cannabis users had lower odds of atrial fibrillation (aOR = 0.902, p < 0.01), ventricular fibrillation (aOR = 0.919, p < 0.01), cardiogenic shock (aOR = 0.730, p < 0.01), acute ischaemic stroke (aOR = 0.825, p < 0.01), cardiac arrest (aOR = 0.936, p = 0.010), undergoing PCI (aOR = 0.826, p < 0.01), using IABP (aOR = 0.835, p < 0.01), and all-cause mortality (aOR = 0.640, p < 0.01), but with higher odds of supraventricular tachycardia (aOR = 1.104, p < 0.01), ventricular tachycardia (aOR = 1.054, p < 0.01), CABG use (aOR = 1.040, p = 0.010), and acute kidney injury (aOR = 1.103, p < 0.01). Conclusions Among patients aged 18-80 years admitted to hospital with AMI between 2001 and 2020 in the United States, cannabis use was associated with lower risks of cardiogenic shock, acute ischaemic stroke, cardiac arrest, PCI use, and in-hospital mortality.
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Affiliation(s)
- Nomesh Kumar
- Department of Internal Medicine, Detroit Medical Center-Wayne State University of Sinai Grace, Michigan, US
| | | | | | - Renuka Verma
- Department of Internal Medicine, Kirk Kerkorian School of Medicine at UNLV, Las Vegas, US
| | | | - Camryn Schroeder
- Medical Student at Kirk Kerkorian School of Medicine at UNLV, Las Vegas, US
| | - Lily Liu
- Medical Student at Kirk Kerkorian School of Medicine at UNLV, Las Vegas, US
| | - Fnu Bawna
- Independent researcher, Farmington Hills, Michigan, US
| | | | - Raheel Ahmed
- Royal Brompton Hospital, part of Guy’s and St. Thomas’ NHS Foundation Trust, London, UK
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10
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Tovar R, de Ceglia M, Rodríguez-Pozo M, Vargas A, Gavito A, Suárez J, Boronat A, de la Torre R, de Fonseca FR, Baixeras E, Decara J. Hydroxytyrosol Linoleoyl Ether Ameliorates Metabolic-Associated Fatty Liver Disease Symptoms in Obese Zucker Rats. ACS Pharmacol Transl Sci 2024; 7:1571-1583. [PMID: 38751648 PMCID: PMC11092116 DOI: 10.1021/acsptsci.4c00105] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/21/2024] [Revised: 03/26/2024] [Accepted: 03/28/2024] [Indexed: 05/18/2024]
Abstract
A main hepatic consequence of obesity is metabolic-associated fatty liver disease (MAFLD), currently treated by improving eating habits and administrating fibrates yet often yielding suboptimal outcomes. Searching for a new therapeutic approach, we aimed to evaluate the efficacy of hydroxytyrosol linoleoyl ether (HTLE), a dual Ppar-α agonist/Cb1 antagonist with inherent antioxidant properties, as an antisteatotic agent. Using lean and obese Zucker rats, they were administrated daily doses of HTLE (3 mg/kg) over a 15-day period, evaluating its safety profile, pharmacokinetics, impact on body weight, hepatic fat content, expression of key enzymes involved in lipogenesis/fatty acid oxidation, and antioxidant capacity. HTLE decreased the body weight and food intake in both rat genotypes. Biochemical analysis demonstrated a favorable safety profile for HTLE along with decreased concentrations of urea, total cholesterol, and aspartate aminotransferase AST transaminases in plasma. Notably, HTLE exhibited potent antisteatotic effects in obese rats, evidenced by a decrease in liver fat content and downregulation of lipogenesis-related enzymes, alongside increased expression of proteins controlling lipid oxidation. Moreover, HTLE successfully counteracted the redox imbalance associated with MAFLD in obese rats, attenuating lipid peroxidation and replenishing both glutathione levels and the overall antioxidant. Our findings highlight the effectiveness of triple-action strategies in managing MAFLD effectively. Based on our results in the Zucker rat model, HTLE emerges as a promising candidate with triple functionality as an anorexigenic, antisteatotic, and antioxidant agent, offering potential relief from MAFLD symptoms associated with obesity while exhibiting minimal side effects. In conclusion, our study positions HTLE as a highly promising compound for therapeutic intervention in MAFLD treatment, warranting further exploration in clinical trials.
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Affiliation(s)
- Rubén Tovar
- Instituto
de Investigación Biomédica de Málaga y Plataforma
en Nanomedicina-IBIMA Plataforma BIONAND, Hospital Universitario Regional de Málaga, UGC Salud Mental, Av. Carlos Haya 82, Málaga 29010, Spain
- Facultad
de Ciencias, Universidad de Málaga,
Campus Universitario de Teatinos s/n, Málaga 29010, Spain
| | - Marialuisa de Ceglia
- Instituto
de Investigación Biomédica de Málaga y Plataforma
en Nanomedicina-IBIMA Plataforma BIONAND, Hospital Universitario Regional de Málaga, UGC Salud Mental, Av. Carlos Haya 82, Málaga 29010, Spain
| | - Miguel Rodríguez-Pozo
- Instituto
de Investigación Biomédica de Málaga y Plataforma
en Nanomedicina-IBIMA Plataforma BIONAND, Hospital Universitario Regional de Málaga, UGC Salud Mental, Av. Carlos Haya 82, Málaga 29010, Spain
| | - Antonio Vargas
- Instituto
de Investigación Biomédica de Málaga y Plataforma
en Nanomedicina-IBIMA Plataforma BIONAND, Hospital Universitario Regional de Málaga, UGC Salud Mental, Av. Carlos Haya 82, Málaga 29010, Spain
| | - Ana Gavito
- Instituto
de Investigación Biomédica de Málaga y Plataforma
en Nanomedicina-IBIMA Plataforma BIONAND, Hospital Universitario Regional de Málaga, UGC Salud Mental, Av. Carlos Haya 82, Málaga 29010, Spain
| | - Juan Suárez
- Instituto
de Investigación Biomédica de Málaga y Plataforma
en Nanomedicina-IBIMA Plataforma BIONAND, Hospital Universitario Regional de Málaga, UGC Salud Mental, Av. Carlos Haya 82, Málaga 29010, Spain
- Departamento
de Anatomía Humana, Medicina Legal e Historia de la Ciencia,
Facultad de Medicina, Universidad de Málaga,
Campus Universitario de Teatinos s/n, Málaga 29010, Spain
| | - Anna Boronat
- Grupo
de Farmacología Integrada y Neurociencia de Sistemas, Programa
de investigación en Neurociencias, Instituto de Investigaciones Médicas Hospital del Mar (IMIM), C/del Dr. Aiguader 88, Barcelona 08003, Spain
| | - Rafael de la Torre
- Grupo
de Farmacología Integrada y Neurociencia de Sistemas, Programa
de investigación en Neurociencias, Instituto de Investigaciones Médicas Hospital del Mar (IMIM), C/del Dr. Aiguader 88, Barcelona 08003, Spain
| | - Fernando Rodríguez de Fonseca
- Instituto
de Investigación Biomédica de Málaga y Plataforma
en Nanomedicina-IBIMA Plataforma BIONAND, Hospital Universitario Regional de Málaga, UGC Salud Mental, Av. Carlos Haya 82, Málaga 29010, Spain
| | - Elena Baixeras
- Departamento
de Bioquímica y Biología Molecular, Facultad de Medicina, Universidad de Málaga, Campus Universitario
de Teatinos s/n, Málaga 29010, Spain
| | - Juan Decara
- Instituto
de Investigación Biomédica de Málaga y Plataforma
en Nanomedicina-IBIMA Plataforma BIONAND, Hospital Universitario Regional de Málaga, UGC Salud Mental, Av. Carlos Haya 82, Málaga 29010, Spain
- Departamento
de Anatomía Humana, Medicina Legal e Historia de la Ciencia,
Facultad de Medicina, Universidad de Málaga,
Campus Universitario de Teatinos s/n, Málaga 29010, Spain
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11
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Bo Y, Zhao X, Li L. Cardiotoxic effects of common and emerging drugs: role of cannabinoid receptors. Clin Sci (Lond) 2024; 138:413-434. [PMID: 38505994 DOI: 10.1042/cs20231156] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/21/2023] [Revised: 02/23/2024] [Accepted: 03/12/2024] [Indexed: 03/21/2024]
Abstract
Drug-induced cardiotoxicity has become one of the most common and detrimental health concerns, which causes significant loss to public health and drug resources. Cannabinoid receptors (CBRs) have recently achieved great attention for their vital roles in the regulation of heart health and disease, with mounting evidence linking CBRs with the pathogenesis and progression of drug-induced cardiotoxicity. This review aims to summarize fundamental characteristics of two well-documented CBRs (CB1R and CB2R) from aspects of molecular structure, signaling and their functions in cardiovascular physiology and pathophysiology. Moreover, we describe the roles of CB1R and CB2R in the occurrence of cardiotoxicity induced by common drugs such as antipsychotics, anti-cancer drugs, marijuana, and some emerging synthetic cannabinoids. We highlight the 'yin-yang' relationship between CB1R and CB2R in drug-induced cardiotoxicity and propose future perspectives for CBR-based translational medicine toward cardiotoxicity curation and clinical monitoring.
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Affiliation(s)
- Yiming Bo
- Department of Forensic Medicine, School of Basic Medical Sciences, Fudan University, Shanghai 200032, China
| | - Xin Zhao
- Department of Cardiology, Shanghai Institute of Cardiovascular Diseases, Zhongshan Hospital, Fudan University, Shanghai 200032, China
| | - Liliang Li
- Department of Forensic Medicine, School of Basic Medical Sciences, Fudan University, Shanghai 200032, China
- Department of Cardiology, Shanghai Institute of Cardiovascular Diseases, Zhongshan Hospital, Fudan University, Shanghai 200032, China
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12
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Abstract
Cannabis, the most commonly used recreational drug, is illicit in many areas of the world. With increasing decriminalization and legalization, cannabis use is increasing in the United States and other countries. The adverse effects of cannabis are unclear because its status as a Schedule 1 drug in the United States restricts research. Despite a paucity of data, cannabis is commonly perceived as a benign or even beneficial drug. However, recent studies show that cannabis has adverse cardiovascular and pulmonary effects and is linked with malignancy. Moreover, case reports have shown an association between cannabis use and neuropsychiatric disorders. With growing availability, cannabis misuse by minors has led to increasing incidences of overdose and toxicity. Though difficult to detect, cannabis intoxication may be linked to impaired driving and motor vehicle accidents. Overall, cannabis use is on the rise, and adverse effects are becoming apparent in clinical data sets.
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Affiliation(s)
- Mark Chandy
- Stanford Cardiovascular Institute, Stanford University School of Medicine, Stanford, California, USA;
- Department of Medicine, Division of Cardiovascular Medicine, Stanford University School of Medicine, Stanford, California, USA
- Institute of Stem Cell Biology and Regenerative Medicine, Stanford University School of Medicine, Stanford, California, USA
- Department of Medicine, Western University, London, Ontario, Canada;
| | - Masataka Nishiga
- Stanford Cardiovascular Institute, Stanford University School of Medicine, Stanford, California, USA;
- Department of Medicine, Division of Cardiovascular Medicine, Stanford University School of Medicine, Stanford, California, USA
- Institute of Stem Cell Biology and Regenerative Medicine, Stanford University School of Medicine, Stanford, California, USA
| | - Tzu-Tang Wei
- Stanford Cardiovascular Institute, Stanford University School of Medicine, Stanford, California, USA;
- Department of Medicine, Division of Cardiovascular Medicine, Stanford University School of Medicine, Stanford, California, USA
- Institute of Stem Cell Biology and Regenerative Medicine, Stanford University School of Medicine, Stanford, California, USA
- Department and Graduate Institute of Pharmacology, College of Medicine, National Taiwan University, Taipei, Taiwan
| | - Naomi M Hamburg
- Boston Medical Center, Boston University Chobanian & Avedisian School of Medicine and Boston University School of Public Health, Boston, Massachusetts, USA
| | - Kari Nadeau
- Department of Environmental Health, Harvard T.H. Chan School of Public Health, Harvard University, Cambridge, Massachusetts, USA
| | - Joseph C Wu
- Stanford Cardiovascular Institute, Stanford University School of Medicine, Stanford, California, USA;
- Department of Medicine, Division of Cardiovascular Medicine, Stanford University School of Medicine, Stanford, California, USA
- Institute of Stem Cell Biology and Regenerative Medicine, Stanford University School of Medicine, Stanford, California, USA
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13
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Rorabaugh BR, Guindon J, Morgan DJ. Role of Cannabinoid Signaling in Cardiovascular Function and Ischemic Injury. J Pharmacol Exp Ther 2023; 387:265-276. [PMID: 37739804 PMCID: PMC10658922 DOI: 10.1124/jpet.123.001665] [Citation(s) in RCA: 5] [Impact Index Per Article: 2.5] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/28/2023] [Revised: 08/14/2023] [Accepted: 09/01/2023] [Indexed: 09/24/2023] Open
Abstract
Cardiovascular disease represents a leading cause of death, morbidity, and societal economic burden. The prevalence of cannabis use has significantly increased due to legalization and an increased societal acceptance of cannabis. Therefore, it is critically important that we gain a greater understanding of the effects and risks of cannabinoid use on cardiovascular diseases as well as the potential for cannabinoid-directed drugs to be used as therapeutics for the treatment of cardiovascular disease. This review summarizes our current understanding of the role of cannabinoid receptors in the pathophysiology of atherosclerosis and myocardial ischemia and explores their use as therapeutic targets in the treatment of ischemic heart disease. Endocannabinoids are elevated in patients with atherosclerosis, and activation of cannabinoid type 1 receptors (CB1Rs) generally leads to an enhancement of plaque formation and atherosclerosis. In contrast, selective activation of cannabinoid type 2 receptors (CB2Rs) appears to exert protective effects against atherosclerosis. Endocannabinoid signaling is also activated by myocardial ischemia. CB2R signaling appears to protect the heart from ischemic injury, whereas the role of CB1R in ischemic injury is less clear. This narrative review serves to summarize current research on the role of cannabinoid signaling in cardiovascular function with the goal of identifying critical knowledge gaps and future studies to address those gaps in a way that facilitates the development of new treatments and better cardiovascular health. SIGNIFICANCE STATEMENT: Cardiovascular diseases, including atherosclerosis and myocardial infarction, are a leading cause of death. Cannabinoid drugs have well known acute effects on cardiovascular function, including tachycardia and orthostatic hypotension. The recent legalization of marijuana and cannabinoids for both medical and recreational use has dramatically increased their prevalence of use. This narrative review on the role of cannabinoid signaling in cardiovascular disease contributes to a better understanding of this topic by integrating current knowledge and identifying critical gaps.
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Affiliation(s)
- Boyd R Rorabaugh
- Department of Biomedical Sciences (D.J.M.) and Department of Pharmaceutical Sciences (B.R.R.), Marshall University, Huntington, West Virginia; and Department of Neuroscience and Pharmacology, Texas Tech University Health Sciences Center, Lubbock, Texas (J.G.)
| | - Josée Guindon
- Department of Biomedical Sciences (D.J.M.) and Department of Pharmaceutical Sciences (B.R.R.), Marshall University, Huntington, West Virginia; and Department of Neuroscience and Pharmacology, Texas Tech University Health Sciences Center, Lubbock, Texas (J.G.)
| | - Daniel J Morgan
- Department of Biomedical Sciences (D.J.M.) and Department of Pharmaceutical Sciences (B.R.R.), Marshall University, Huntington, West Virginia; and Department of Neuroscience and Pharmacology, Texas Tech University Health Sciences Center, Lubbock, Texas (J.G.)
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14
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Bányai B, Vass Z, Kiss S, Balogh A, Brandhuber D, Karvaly G, Kovács K, Nádasy GL, Hunyady L, Dörnyei G, Horváth EM, Szekeres M. Role of CB1 Cannabinoid Receptors in Vascular Responses and Vascular Remodeling of the Aorta in Female Mice. Int J Mol Sci 2023; 24:16429. [PMID: 38003619 PMCID: PMC10671338 DOI: 10.3390/ijms242216429] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/13/2023] [Revised: 10/31/2023] [Accepted: 11/07/2023] [Indexed: 11/26/2023] Open
Abstract
Both the endocannabinoid system (ECS) and estrogens have significant roles in cardiovascular control processes. Cannabinoid type 1 receptors (CB1Rs) mediate acute vasodilator and hypotensive effects, although their role in cardiovascular pathological conditions is still controversial. Estrogens exert cardiovascular protection in females. We aimed to study the impact of ECS on vascular functions. Experiments were performed on CB1R knockout (CB1R KO) and wild-type (WT) female mice. Plasma estrogen metabolite levels were determined. Abdominal aortas were isolated for myography and histology. Vascular effects of phenylephrine (Phe), angiotensin II, acetylcholine (Ach) and estradiol (E2) were obtained and repeated with inhibitors of nitric oxide synthase (NOS, Nω-nitro-L-arginine) and of cyclooxygenase (COX, indomethacin). Histological stainings (hematoxylin-eosin, resorcin-fuchsin) and immunostainings for endothelial NOS (eNOS), COX-2, estrogen receptors (ER-α, ER-β) were performed. Conjugated E2 levels were higher in CB1R KO compared to WT mice. Vasorelaxation responses to Ach and E2 were increased in CB1R KO mice, attenuated by NOS-inhibition. COX-inhibition decreased Phe-contractions, while it increased Ach-relaxation in the WT group but not in the CB1R KO. Effects of indomethacin on E2-relaxation in CB1R KO became opposite to that observed in WT. Histology revealed lower intima/media thickness and COX-2 density, higher eNOS and lower ER-β density in CB1R KO than in WT mice. CB1R KO female mice are characterized by increased vasorelaxation associated with increased utilization of endothelial NO and a decreased impact of constrictor prostanoids. Our results indicate that the absence or inhibition of CB1Rs may have beneficial vascular effects.
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Affiliation(s)
- Bálint Bányai
- Department of Physiology, Faculty of Medicine, Semmelweis University, 37-47 Tűzoltó Street, 1094 Budapest, Hungary; (B.B.); (S.K.); (G.L.N.); (L.H.); (E.M.H.)
| | - Zsolt Vass
- Department of Morphology and Physiology, Faculty of Health Sciences, Semmelweis University, 17 Vas Street, 1088 Budapest, Hungary; (Z.V.); (A.B.); (D.B.)
| | - Stella Kiss
- Department of Physiology, Faculty of Medicine, Semmelweis University, 37-47 Tűzoltó Street, 1094 Budapest, Hungary; (B.B.); (S.K.); (G.L.N.); (L.H.); (E.M.H.)
- Department of Morphology and Physiology, Faculty of Health Sciences, Semmelweis University, 17 Vas Street, 1088 Budapest, Hungary; (Z.V.); (A.B.); (D.B.)
| | - Anikó Balogh
- Department of Morphology and Physiology, Faculty of Health Sciences, Semmelweis University, 17 Vas Street, 1088 Budapest, Hungary; (Z.V.); (A.B.); (D.B.)
| | - Dóra Brandhuber
- Department of Morphology and Physiology, Faculty of Health Sciences, Semmelweis University, 17 Vas Street, 1088 Budapest, Hungary; (Z.V.); (A.B.); (D.B.)
| | - Gellért Karvaly
- Department of Laboratory Medicine, Faculty of Medicine, Semmelweis University, 4 Nagyvárad Square, 1089 Budapest, Hungary; (G.K.); (K.K.)
| | - Krisztián Kovács
- Department of Laboratory Medicine, Faculty of Medicine, Semmelweis University, 4 Nagyvárad Square, 1089 Budapest, Hungary; (G.K.); (K.K.)
| | - György L. Nádasy
- Department of Physiology, Faculty of Medicine, Semmelweis University, 37-47 Tűzoltó Street, 1094 Budapest, Hungary; (B.B.); (S.K.); (G.L.N.); (L.H.); (E.M.H.)
| | - László Hunyady
- Department of Physiology, Faculty of Medicine, Semmelweis University, 37-47 Tűzoltó Street, 1094 Budapest, Hungary; (B.B.); (S.K.); (G.L.N.); (L.H.); (E.M.H.)
- Institute of Enzymology, HUN-REN Research Centre for Natural Sciences, 2 Magyar Tudósok Körútja, 1117 Budapest, Hungary
| | - Gabriella Dörnyei
- Department of Morphology and Physiology, Faculty of Health Sciences, Semmelweis University, 17 Vas Street, 1088 Budapest, Hungary; (Z.V.); (A.B.); (D.B.)
| | - Eszter Mária Horváth
- Department of Physiology, Faculty of Medicine, Semmelweis University, 37-47 Tűzoltó Street, 1094 Budapest, Hungary; (B.B.); (S.K.); (G.L.N.); (L.H.); (E.M.H.)
| | - Mária Szekeres
- Department of Physiology, Faculty of Medicine, Semmelweis University, 37-47 Tűzoltó Street, 1094 Budapest, Hungary; (B.B.); (S.K.); (G.L.N.); (L.H.); (E.M.H.)
- Department of Morphology and Physiology, Faculty of Health Sciences, Semmelweis University, 17 Vas Street, 1088 Budapest, Hungary; (Z.V.); (A.B.); (D.B.)
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15
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Liu F, Wang Y, Yu J. Role of inflammation and immune response in atherosclerosis: Mechanisms, modulations, and therapeutic targets. Hum Immunol 2023; 84:439-449. [PMID: 37353446 DOI: 10.1016/j.humimm.2023.06.002] [Citation(s) in RCA: 5] [Impact Index Per Article: 2.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/21/2023] [Revised: 05/19/2023] [Accepted: 06/08/2023] [Indexed: 06/25/2023]
Abstract
Cardiovascular diseases (CVDs) have emerged as the leading cause of mortality globally, with atherosclerosis being a prominent focus of investigation among medical researchers worldwide. Atherosclerosis is characterized as a disease of the large and medium-sized arteries that is multifocal, accumulative, and immunoinflammatory in nature, resulting from the deposition of lipids. Accumulating evidence suggests that inflammatory responses and immunoregulation play a vital role in the occurrence and development of atherosclerosis. While existing treatments for atherosclerosis can assist in symptom management and slowing disease progression, a complete cure remains elusive. Consequently, there is significant interest in research and development of potential new drugs for this condition. Therefore, this review aims to consolidate the current understanding of the pathogenesis of atherosclerosis with an emphasis on inflammation, immune response and infection. Besides, it examines the effects and mechanisms of immunological modulations in atherosclerosis, and the potential therapeutic targets and drugs for intervening in the inflammatory responses and immunoregulation associated with atherosclerosis. Additionally, novel drug options for treating atherosclerosis are explored within the context of this review.
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Affiliation(s)
- Fang Liu
- Department of Vascular Surgery, Affiliated Hospital of Jiangsu University, Zhenjiang 212001, China; International Genome Center, Jiangsu University, Zhenjiang 212013, China.
| | - Yijun Wang
- International Genome Center, Jiangsu University, Zhenjiang 212013, China
| | - Jiayin Yu
- International Genome Center, Jiangsu University, Zhenjiang 212013, China
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16
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Pati B, Sendh S, Sahu B, Pani S, Jena N, Bal NC. Recent advancements in pharmacological strategies to modulate energy balance for combating obesity. RSC Med Chem 2023; 14:1429-1445. [PMID: 37593583 PMCID: PMC10429841 DOI: 10.1039/d3md00107e] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/06/2023] [Accepted: 06/06/2023] [Indexed: 08/19/2023] Open
Abstract
The prevalence of obesity along with its related metabolic diseases has increased globally in recent decades. Obesity originates from a heterogeneous physiological state, which is further complicated by the influence of factors such as genetic, behavioural, and environmental. Lifestyle interventions including exercise and diet have limited success, necessitating the development of pharmacological approaches. Mechanistically, strategies target either reducing energy intake or increasing consumption through metabolism boosting. Current drugs lower energy intake via inducing satiety or inhibiting substrate absorption, while targeting mitochondria or cytosolic energy sensors has shown limited success due to toxicity. Nonshivering thermogenesis (NST) has provided hope for activating these processes selectively without significant side effects. The internet-based marketing of plant-based formulations for enhancing metabolism has surged. This review compiles scientific articles, magazines, newspapers, and online resources on anti-obesity drug development. Combination therapy of metabolic boosters and established anti-obesity compounds appears to be a promising future approach that requires further research.
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Affiliation(s)
- Benudhara Pati
- School of Biotechnology, KIIT University Bhubaneswar Odisha 751024 India
| | - Satyabrata Sendh
- School of Biotechnology, KIIT University Bhubaneswar Odisha 751024 India
| | - Bijayashree Sahu
- School of Biotechnology, KIIT University Bhubaneswar Odisha 751024 India
| | - Sunil Pani
- School of Biotechnology, KIIT University Bhubaneswar Odisha 751024 India
| | - Nivedita Jena
- Institute of Life Science, DBT ILS Bioincubator Bhubaneswar Odisha 751021-India
| | - Naresh Chandra Bal
- School of Biotechnology, KIIT University Bhubaneswar Odisha 751024 India
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17
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Musetti B, Bahnson EM, Thomson L. Cannabinoids in inflammation and atherosclerosis. MEDICINAL USAGE OF CANNABIS AND CANNABINOIDS 2023:159-169. [DOI: 10.1016/b978-0-323-90036-2.00016-8] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 01/03/2025]
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18
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Ghasemi-Gojani E, Kovalchuk I, Kovalchuk O. Cannabinoids and terpenes for diabetes mellitus and its complications: from mechanisms to new therapies. Trends Endocrinol Metab 2022; 33:828-849. [PMID: 36280497 DOI: 10.1016/j.tem.2022.08.003] [Citation(s) in RCA: 7] [Impact Index Per Article: 2.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 07/26/2022] [Accepted: 08/29/2022] [Indexed: 11/05/2022]
Abstract
The number of people diagnosed with diabetes mellitus and its complications is markedly increasing worldwide, leading to a worldwide epidemic across all age groups, from children to older adults. Diabetes is associated with premature aging. In recent years, it has been found that peripheral overactivation of the endocannabinoid system (ECS), and in particular cannabinoid receptor 1 (CB1R) signaling, plays a crucial role in the progression of insulin resistance, diabetes (especially type 2), and its aging-related comorbidities such as atherosclerosis, nephropathy, neuropathy, and retinopathy. Therefore, it is suggested that peripheral blockade of CB1R may ameliorate diabetes and diabetes-related comorbidities. The use of synthetic CB1R antagonists such as rimonabant has been prohibited because of their psychiatric side effects. In contrast, phytocannabinoids such as cannabidiol (CBD) and tetrahydrocannabivarin (THCV), produced by cannabis, exhibit antagonistic activity on CB1R signaling and do not show any adverse side effects such as psychoactive effects, depression, or anxiety, thereby serving as potential candidates for the treatment of diabetes and its complications. In addition to these phytocannabinoids, cannabis also produces a substantial number of other phytocannabinoids, terpenes, and flavonoids with therapeutic potential against insulin resistance, diabetes, and its complications. In this review, the pathogenesis of diabetes, its complications, and the potential to use cannabinoids, terpenes, and flavonoids for its treatment are discussed.
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Affiliation(s)
| | - Igor Kovalchuk
- University of Lethbridge, Lethbridge, AB T1K3M4, Canada.
| | - Olga Kovalchuk
- University of Lethbridge, Lethbridge, AB T1K3M4, Canada.
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19
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Rajesh M, Mukhopadhyay P, Bátkai S, Arif M, Varga ZV, Mátyás C, Paloczi J, Lehocki A, Haskó G, Pacher P. Cannabinoid receptor 2 activation alleviates diabetes-induced cardiac dysfunction, inflammation, oxidative stress, and fibrosis. GeroScience 2022; 44:1727-1741. [PMID: 35460032 PMCID: PMC9213632 DOI: 10.1007/s11357-022-00565-9] [Citation(s) in RCA: 17] [Impact Index Per Article: 5.7] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/23/2022] [Accepted: 04/04/2022] [Indexed: 11/29/2022] Open
Abstract
Diabetes mellitus promotes accelerated cardiovascular aging and inflammation, which in turn facilitate the development of cardiomyopathy/heart failure. High glucose-induced oxidative/nitrative stress, activation of various pro-inflammatory, and cell death pathways are critical in the initiation and progression of the changes culminating in diabetic cardiomyopathy. Cannabinoid 2 receptor (CB2R) activation in inflammatory cells and activated endothelium attenuates the pathological changes associated with atherosclerosis, myocardial infarction, stroke, and hepatic cardiomyopathy. In this study, we explored the role of CB2R signaling in myocardial dysfunction, oxidative/nitrative stress, inflammation, cell death, remodeling, and fibrosis associated with diabetic cardiomyopathy in type 1 diabetic mice. Control human heart left ventricles and atrial appendages, similarly to mouse hearts, had negligible CB2R expression determine by RNA sequencing or real-time RT-PCR. Diabetic cardiomyopathy was characterized by impaired diastolic and systolic cardiac function, enhanced myocardial CB2R expression, oxidative/nitrative stress, and pro-inflammatory response (tumor necrosis factor-α, interleukin-1β, intracellular adhesion molecule 1, macrophage inflammatory protein-1, monocyte chemoattractant protein-1), macrophage infiltration, fibrosis, and cell death. Pharmacological activation of CB2R with a selective agonist attenuated diabetes-induced inflammation, oxidative/nitrative stress, fibrosis and cell demise, and consequent cardiac dysfunction without affecting hyperglycemia. In contrast, genetic deletion of CB2R aggravated myocardial pathology. Thus, selective activation of CB2R ameliorates diabetes-induced myocardial tissue injury and preserves the functional contractile capacity of the myocardium in the diabetic milieu. This is particularly encouraging, since unlike CB1R agonists, CB2R agonists do not elicit psychoactive activity and cardiovascular side effects and are potential clinical candidates in the treatment of diabetic cardiovascular and other complications.
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Affiliation(s)
- Mohanraj Rajesh
- Laboratory of Cardiovascular Physiology and Tissue Injury, National Institute On Alcohol Abuse and Alcoholism, National Institutes of Health, Bethesda, MD, USA
| | - Partha Mukhopadhyay
- Laboratory of Cardiovascular Physiology and Tissue Injury, National Institute On Alcohol Abuse and Alcoholism, National Institutes of Health, Bethesda, MD, USA
| | - Sándor Bátkai
- Laboratory of Cardiovascular Physiology and Tissue Injury, National Institute On Alcohol Abuse and Alcoholism, National Institutes of Health, Bethesda, MD, USA
| | - Muhammad Arif
- Laboratory of Cardiovascular Physiology and Tissue Injury, National Institute On Alcohol Abuse and Alcoholism, National Institutes of Health, Bethesda, MD, USA
| | - Zoltán V Varga
- Laboratory of Cardiovascular Physiology and Tissue Injury, National Institute On Alcohol Abuse and Alcoholism, National Institutes of Health, Bethesda, MD, USA
- Department of Pharmacology and Pharmacotherapy, Semmelweis University, Budapest, Hungary
| | - Csaba Mátyás
- Laboratory of Cardiovascular Physiology and Tissue Injury, National Institute On Alcohol Abuse and Alcoholism, National Institutes of Health, Bethesda, MD, USA
| | - Janos Paloczi
- Laboratory of Cardiovascular Physiology and Tissue Injury, National Institute On Alcohol Abuse and Alcoholism, National Institutes of Health, Bethesda, MD, USA
| | - Andrea Lehocki
- Departments of Hematology and Stem Cell Transplantation, South Pest Central Hospital, National Institute of Hematology and Infectious Diseases, Saint Ladislaus Campus, Budapest, Hungary
| | - György Haskó
- Department of Anesthesiology, Columbia University, New York, NY, USA
| | - Pal Pacher
- Laboratory of Cardiovascular Physiology and Tissue Injury, National Institute On Alcohol Abuse and Alcoholism, National Institutes of Health, Bethesda, MD, USA.
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20
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El-Azab MF, Wakiel AE, Nafea YK, Youssef ME. Role of cannabinoids and the endocannabinoid system in modulation of diabetic cardiomyopathy. World J Diabetes 2022; 13:387-407. [PMID: 35664549 PMCID: PMC9134026 DOI: 10.4239/wjd.v13.i5.387] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 05/31/2021] [Revised: 07/18/2021] [Accepted: 04/28/2022] [Indexed: 02/06/2023] Open
Abstract
Diabetic complications, chiefly seen in long-term situations, are persistently deleterious to a large extent, requiring multi-factorial risk reduction strategies beyond glycemic control. Diabetic cardiomyopathy is one of the most common deleterious diabetic complications, being the leading cause of mortality among diabetic patients. The mechanisms of diabetic cardiomyopathy are multi-factorial, involving increased oxidative stress, accumulation of advanced glycation end products (AGEs), activation of various pro-inflammatory and cell death signaling pathways, and changes in the composition of extracellular matrix with enhanced cardiac fibrosis. The novel lipid signaling system, the endocannabinoid system, has been implicated in the pathogenesis of diabetes and its complications through its two main receptors: Cannabinoid receptor type 1 and cannabinoid receptor type 2, alongside other components. However, the role of the endocannabinoid system in diabetic cardiomyopathy has not been fully investigated. This review aims to elucidate the possible mechanisms through which cannabinoids and the endocannabinoid system could interact with the pathogenesis and the development of diabetic cardiomyopathy. These mechanisms include oxidative/ nitrative stress, inflammation, accumulation of AGEs, cardiac remodeling, and autophagy. A better understanding of the role of cannabinoids and the endocannabinoid system in diabetic cardiomyopathy may provide novel strategies to manipulate such a serious diabetic complication.
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Affiliation(s)
- Mona F El-Azab
- Department of Pharmacology and Toxicology, Faculty of Pharmacy, Suez Canal University, Ismailia 41522, Egypt
| | - Ahmed E Wakiel
- Department of Pharmacology and Toxicology, Faculty of Pharmacy, Suez Canal University, Ismailia 41522, Egypt
| | - Yossef K Nafea
- Program of Biochemistry, McMaster University, Hamilton L8S 4L8, Ontario, Canada
| | - Mahmoud E Youssef
- Department of Pharmacology and Biochemistry, Delta University for Science and Technology, Mansoura 35511, New Cairo, Egypt
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21
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Potential Implications of Rimonabant on Age-Related Oxidative Stress and Inflammation. Antioxidants (Basel) 2022; 11:antiox11010162. [PMID: 35052666 PMCID: PMC8773212 DOI: 10.3390/antiox11010162] [Citation(s) in RCA: 3] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/15/2021] [Revised: 01/11/2022] [Accepted: 01/12/2022] [Indexed: 02/01/2023] Open
Abstract
Over the last decades, growing interest has turned to preventive and therapeutic approaches for achieving successful aging. Oxidative stress and inflammation are fundamental features of cardiovascular diseases; therefore, potential targets of them can improve cardiac outcomes. Our study aimed to examine the involvement of the endocannabinoid system, especially the CB1 receptor blockade, on inflammatory and oxidant/antioxidant processes. Twenty-month-old female and male Wistar rats were divided into rimonabant-treated and aging control (untreated) groups. Rimonabant, a selective CB1 receptor antagonist, was administered at the dose of 1 mg/kg/day intraperitoneally for 2 weeks. Cardiac amounts of ROS, the antioxidant glutathione and superoxide dismutase (SOD), and the activity and concentration of the heme oxygenase (HO) enzyme were detected. Among inflammatory parameters, nuclear factor-kappa B (NF-κB), tumor necrosis factor-alpha (TNF-α), and myeloperoxidase (MPO) enzyme activity were measured. Two weeks of low dose rimonabant treatment significantly reduced the cardiac ROS via boosting of the antioxidant defense mechanisms as regards the HO system, and the SOD and glutathione content. Consistently, the age-related inflammatory response was alleviated. Rimonabant-treated animals showed significantly decreased NF-κB, TNF-α, and MPO levels. Our findings prove the beneficial involvement of CB1 receptor blocker rimonabant on inflammatory and oxidative damages to the aging heart.
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22
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Khan RN, Maner-Smith K, A. Owens J, Barbian ME, Jones RM, R. Naudin C. At the heart of microbial conversations: endocannabinoids and the microbiome in cardiometabolic risk. Gut Microbes 2022; 13:1-21. [PMID: 33896380 PMCID: PMC8078674 DOI: 10.1080/19490976.2021.1911572] [Citation(s) in RCA: 10] [Impact Index Per Article: 3.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 02/07/2023] Open
Abstract
Cardiometabolic syndrome encompasses intertwined risk factors such as hypertension, dyslipidemia, elevated triglycerides, abdominal obesity, and other maladaptive metabolic and inflammatory aberrations. As the molecular mechanisms linking cardiovascular disease and metabolic disorders are investigated, endocannabinoids have emerged as molecules of interest. The endocannabinoid system (ECS) of biologically active lipids has been implicated in several conditions, including chronic liver disease, osteoporosis, and more recently in cardiovascular diseases. The gut microbiome is a major regulator of inflammatory and metabolic signaling in the host, and if disrupted, has the potential to drive metabolic and cardiovascular diseases. Extensive studies have unraveled the impact of the gut microbiome on host physiology, with recent reports showing that gut microbes exquisitely control the ECS, with significant influences on host metabolic and cardiac health. In this review, we outline how modulation of the gut microbiome affects host metabolism and cardiovascular health via the ECS, and how these findings could be exploited as novel therapeutic targets for various metabolic and cardiac diseases.
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Affiliation(s)
- Ramsha Nabihah Khan
- Division of Gastroenterology and Hepatology, Department of Pediatrics, Children’s Healthcare of Atlanta and Emory University, Atlanta, Georgia, USA
| | - Kristal Maner-Smith
- Emory Integrated Metabolomics and Lipidomics Core, Emory University, Atlanta, Georgia, USA
| | - Joshua A. Owens
- Division of Gastroenterology and Hepatology, Department of Pediatrics, Children’s Healthcare of Atlanta and Emory University, Atlanta, Georgia, USA
| | - Maria Estefania Barbian
- Division of Neonatology, Department of Pediatrics, Children’s Healthcare of Atlanta and Emory University, Atlanta, Georgia, USA
| | - Rheinallt M. Jones
- Division of Gastroenterology and Hepatology, Department of Pediatrics, Children’s Healthcare of Atlanta and Emory University, Atlanta, Georgia, USA
| | - Crystal R. Naudin
- Division of Gastroenterology and Hepatology, Department of Pediatrics, Children’s Healthcare of Atlanta and Emory University, Atlanta, Georgia, USA,CONTACT Crystal R. Naudin Division of Gastroenterology, Hepatology, and Nutrition, Department of Pediatrics, Emory University School of Medicine, 615 Michael Street, Atlanta, GA30322, United States of America
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23
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Rabino M, Mallia S, Castiglioni E, Rovina D, Pompilio G, Gowran A. The Endocannabinoid System and Cannabidiol: Past, Present, and Prospective for Cardiovascular Diseases. Pharmaceuticals (Basel) 2021; 14:ph14090936. [PMID: 34577636 PMCID: PMC8472406 DOI: 10.3390/ph14090936] [Citation(s) in RCA: 4] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/11/2021] [Revised: 09/09/2021] [Accepted: 09/13/2021] [Indexed: 12/18/2022] Open
Abstract
In the past, cannabis was commonly associated with mysticism and illegality. Fortunately, in recent years perspectives and discourses have changed. More prominence has been given to the rigorous scientific effort that led to the discovery of cannabis' many physiological actions and endogenous signalling mechanisms. The endocannabinoid system is a complex and heterogeneous pro-homeostatic network comprising different receptors with several endogenous ligands, numerous metabolic enzymes and regulatory proteins. Therefore, it is not surprising that alterations and dysfunctions of the endocannabinoid system are observed in almost every category of disease. Such high degree of pathophysiological involvement suggests the endocannabinoid system is a promising therapeutic target and prompted the translation of resurgent scientific findings into clinical therapies. Shifting attitudes toward cannabis also raised other matters such as increased patient awareness, prescription requests, self-medication, recreational use, recognition of new knowledge gaps, renewed scientific activity, and seemingly exponential growth of the cannabis industry. This review, following a general overview of cannabis and the endocannabinoid system, assiduously describes its role within the context of cardiovascular diseases, paying particular attention to the Janus influence that endocannabinoid system modulators can have on the cardiovascular system.
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Affiliation(s)
- Martina Rabino
- Unit of Vascular Biology and Regenerative Medicine, Centro Cardiologico Monzino-IRCCS, 20138 Milan, Italy
| | - Sara Mallia
- Unit of Vascular Biology and Regenerative Medicine, Centro Cardiologico Monzino-IRCCS, 20138 Milan, Italy
| | - Elisa Castiglioni
- Unit of Vascular Biology and Regenerative Medicine, Centro Cardiologico Monzino-IRCCS, 20138 Milan, Italy
| | - Davide Rovina
- Unit of Vascular Biology and Regenerative Medicine, Centro Cardiologico Monzino-IRCCS, 20138 Milan, Italy
| | - Giulio Pompilio
- Unit of Vascular Biology and Regenerative Medicine, Centro Cardiologico Monzino-IRCCS, 20138 Milan, Italy
- Department of Cardiac Surgery, Centro Cardiologico Monzino-IRCCS, 20138 Milan, Italy
- Department of Biomedical, Surgical and Dental Sciences, University of Milan, 20138 Milan, Italy
| | - Aoife Gowran
- Unit of Vascular Biology and Regenerative Medicine, Centro Cardiologico Monzino-IRCCS, 20138 Milan, Italy
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24
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Lee DI, Murninkas M, Elyagon S, Etzion Y, Anderson HD. Cannabinoid Receptor Agonist Inhibits Atrial Electrical Remodeling in a Tachypaced Ex Vivo Rat Model. Front Pharmacol 2021; 12:642398. [PMID: 33967775 PMCID: PMC8100753 DOI: 10.3389/fphar.2021.642398] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/16/2020] [Accepted: 03/16/2021] [Indexed: 12/17/2022] Open
Abstract
Introduction: Atrial fibrillation (AF) leads to rate-dependent atrial changes collectively defined as atrial remodelling (AR). Shortening of the atrial effective refractory period (AERP) and decreased conduction velocity are among the hallmarks of AR. Pharmacological strategies to inhibit AR, thereby reducing the self-perpetual nature of AF, are of great clinical value. Cannabinoid receptor (CBR) ligands may exert cardioprotective effects; CB13, a dual CBR agonist with limited brain penetration, protects cardiomyocytes from mitochondrial dysfunction induced by endothelin-1. Here, we examined the effects of CB13 on normal physiology of the rat heart and development of tachypacing-induced AR. Methods: Rat hearts were perfused in a Langendorff set-up with CB13 (1 µM) or vehicle. Hemodynamic properties of non-paced hearts were examined conventionally. In a different set of hearts, programmed stimulation protocol was performed before and after atrial tachypacing for 90 min using a mini-hook platinum quadrupole electrode inserted on the right atrium. Atrial samples were further assessed by western blot analysis. Results: CB13 had no effects on basal hemodynamic properties. However, the compound inhibited tachypacing-induced shortening of the AERP. Protein expression of PGC1α was significantly increased by CB13 compared to vehicle in paced and non-paced hearts. Phosphorylation of AMPKα at residue threonine 172 was increased suggesting upregulation of mitochondrial biogenesis. Connexin43 was downregulated by tachypacing. This effect was diminished in the presence of CB13. Conclusion: Our findings support the notion that peripheral activation of CBR may be a new treatment strategy to prevent AR in patients suffering from AF, and therefore warrants further study.
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Affiliation(s)
- Danielle I Lee
- College of Pharmacy, Rady Faculty of Health Sciences, University of Manitoba, Winnipeg, MB, Canada.,Canadian Centre for Agri-Food Research in Health and Medicine (CCARM), Albrechtsen Research Centre, St Boniface Hospital, Winnipeg, MB, Canada
| | - Michael Murninkas
- Cardiac Arrhythmia Research Laboratory, Department of Physiology and Cell Biology, Faculty of Health Sciences, Ben-Gurion University of the Negev, Beer-Sheva, Israel.,Regenerative Medicine and Stem Cell Research Center, Ben-Gurion University of the Negev, Beer-Sheva, Israel
| | - Sigal Elyagon
- Cardiac Arrhythmia Research Laboratory, Department of Physiology and Cell Biology, Faculty of Health Sciences, Ben-Gurion University of the Negev, Beer-Sheva, Israel.,Regenerative Medicine and Stem Cell Research Center, Ben-Gurion University of the Negev, Beer-Sheva, Israel
| | - Yoram Etzion
- Cardiac Arrhythmia Research Laboratory, Department of Physiology and Cell Biology, Faculty of Health Sciences, Ben-Gurion University of the Negev, Beer-Sheva, Israel.,Regenerative Medicine and Stem Cell Research Center, Ben-Gurion University of the Negev, Beer-Sheva, Israel
| | - Hope D Anderson
- College of Pharmacy, Rady Faculty of Health Sciences, University of Manitoba, Winnipeg, MB, Canada.,Canadian Centre for Agri-Food Research in Health and Medicine (CCARM), Albrechtsen Research Centre, St Boniface Hospital, Winnipeg, MB, Canada
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25
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van Eenige R, Ying Z, Tambyrajah L, Pronk ACM, Blomberg N, Giera M, Wang Y, Coskun T, van der Stelt M, Rensen PCN, Kooijman S. Cannabinoid type 1 receptor inverse agonism attenuates dyslipidemia and atherosclerosis in APOE∗3-Leiden.CETP mice. J Lipid Res 2021; 62:100070. [PMID: 33766515 PMCID: PMC8082266 DOI: 10.1016/j.jlr.2021.100070] [Citation(s) in RCA: 10] [Impact Index Per Article: 2.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/03/2021] [Accepted: 03/12/2021] [Indexed: 11/25/2022] Open
Abstract
Pharmacological blockade of the cannabinoid type 1 receptor, a G protein-coupled receptor expressed in the central nervous system and various peripheral tissues, reverses diet-induced obesity and dyslipidemia through the reduction of food intake and altered nutrient partitioning. This strategy is being explored for a number of therapeutic applications; however, its potency for the treatment of atherosclerotic cardiovascular disease via improvements in lipid metabolism remains unclear. Therefore, here, we aimed to investigate whether inhibition of the endocannabinoid system can attenuate atherosclerosis development through improvement of dyslipidemia. Lean, dyslipidemic female APOE∗3-Leiden.CETP transgenic mice were fed a Western-type diet supplemented with or without the cannabinoid type 1 receptor inverse agonist rimonabant (20 mg·kg body weight-1 day-1) for up to 20 weeks. Plasma lipids and bile acids were determined, and atherosclerotic lesions were scored in the aortic valve region. Rimonabant lowered plasma levels of triglyceride (TG) (-56%) and non-HDL-C (-19%) and increased HDL-C (+57%). These effects were explained by decreased VLDL-TG production (-52%) and accelerated VLDL-TG turnover accompanied by pronounced browning of white adipose tissue. In addition, rimonabant attenuated reverse cholesterol transport (-30%), increased plasma bile acid levels (+160%), and increased hepatic cholesterol accumulation (+88%). Importantly, rimonabant markedly lowered atherosclerotic lesion size (-64%), which coincided with decreased lesion severity (28% vs. 56% severe lesions) and which strongly correlated with non-HDL-C exposure (R2 = 0.60). Taken together, inhibition of the endocannabinoid system potently reverses dyslipidemia and prevents atherogenesis, even in the absence of obesity.
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Affiliation(s)
- Robin van Eenige
- Department of Medicine, Division of Endocrinology, and Einthoven Laboratory for Experimental Vascular Medicine, Leiden University Medical Center, Leiden, The Netherlands
| | - Zhixiong Ying
- Department of Medicine, Division of Endocrinology, and Einthoven Laboratory for Experimental Vascular Medicine, Leiden University Medical Center, Leiden, The Netherlands
| | - Lauren Tambyrajah
- Department of Medicine, Division of Endocrinology, and Einthoven Laboratory for Experimental Vascular Medicine, Leiden University Medical Center, Leiden, The Netherlands
| | - Amanda C M Pronk
- Department of Medicine, Division of Endocrinology, and Einthoven Laboratory for Experimental Vascular Medicine, Leiden University Medical Center, Leiden, The Netherlands
| | - Niek Blomberg
- Center for Proteomics & Metabolomics, Leiden University Medical Center, Leiden, The Netherlands
| | - Martin Giera
- Center for Proteomics & Metabolomics, Leiden University Medical Center, Leiden, The Netherlands
| | - Yanan Wang
- Department of Medicine, Division of Endocrinology, and Einthoven Laboratory for Experimental Vascular Medicine, Leiden University Medical Center, Leiden, The Netherlands; Center for Immunological and Metabolic Diseases, MED-X institute, and Department of Endocrinology, the First Affiliated Hospital of Xi'an Jiaotong University, Xi'an, China
| | - Tamer Coskun
- Department of Diabetes/Endocrine, Lilly Research Laboratories, Lilly Corporate Center, Indianapolis, IN, USA
| | - Mario van der Stelt
- Department of Molecular Physiology, Leiden Institute of Chemistry, Leiden University, Leiden, The Netherlands
| | - Patrick C N Rensen
- Department of Medicine, Division of Endocrinology, and Einthoven Laboratory for Experimental Vascular Medicine, Leiden University Medical Center, Leiden, The Netherlands; Center for Immunological and Metabolic Diseases, MED-X institute, and Department of Endocrinology, the First Affiliated Hospital of Xi'an Jiaotong University, Xi'an, China.
| | - Sander Kooijman
- Department of Medicine, Division of Endocrinology, and Einthoven Laboratory for Experimental Vascular Medicine, Leiden University Medical Center, Leiden, The Netherlands
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26
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Suryavanshi SV, Kovalchuk I, Kovalchuk O. Cannabinoids as Key Regulators of Inflammasome Signaling: A Current Perspective. Front Immunol 2021; 11:613613. [PMID: 33584697 PMCID: PMC7876066 DOI: 10.3389/fimmu.2020.613613] [Citation(s) in RCA: 46] [Impact Index Per Article: 11.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/02/2020] [Accepted: 12/10/2020] [Indexed: 12/15/2022] Open
Abstract
Inflammasomes are cytoplasmic inflammatory signaling protein complexes that detect microbial materials, sterile inflammatory insults, and certain host-derived elements. Inflammasomes, once activated, promote caspase-1–mediated maturation and secretion of pro-inflammatory cytokines, interleukin (IL)-1β and IL-18, leading to pyroptosis. Current advances in inflammasome research support their involvement in the development of chronic inflammatory disorders in contrast to their role in regulating innate immunity. Cannabis (marijuana) is a natural product obtained from the Cannabis sativa plant, and pharmacologically active ingredients of the plant are referred to as cannabinoids. Cannabinoids and cannabis extracts have recently emerged as promising novel drugs for chronic medical conditions. Growing evidence indicates the potent anti-inflammatory potential of cannabinoids, especially Δ9-tetrahydrocannabinol (Δ9-THC), cannabidiol (CBD), and synthetic cannabinoids; however, the mechanisms remain unclear. Several attempts have been made to decipher the role of cannabinoids in modulating inflammasome signaling in the etiology of chronic inflammatory diseases. In this review, we discuss recently published evidence on the effect of cannabinoids on inflammasome signaling. We also discuss the contribution of various cannabinoids in human diseases concerning inflammasome regulation. Lastly, in the milieu of coronavirus disease-2019 (COVID-19) pandemic, we confer available evidence linking inflammasome activation to the pathophysiology of COVID-19 suggesting overall, the importance of cannabinoids as possible drugs to target inflammasome activation in or to support the treatment of a variety of human disorders including COVID-19.
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Affiliation(s)
| | - Igor Kovalchuk
- Department of Biological Sciences, University of Lethbridge, Lethbridge, AB, Canada
| | - Olga Kovalchuk
- Department of Biological Sciences, University of Lethbridge, Lethbridge, AB, Canada
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27
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Leuti A, Fazio D, Fava M, Piccoli A, Oddi S, Maccarrone M. Bioactive lipids, inflammation and chronic diseases. Adv Drug Deliv Rev 2020; 159:133-169. [PMID: 32628989 DOI: 10.1016/j.addr.2020.06.028] [Citation(s) in RCA: 213] [Impact Index Per Article: 42.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/03/2020] [Revised: 06/09/2020] [Accepted: 06/25/2020] [Indexed: 02/08/2023]
Abstract
Endogenous bioactive lipids are part of a complex network that modulates a plethora of cellular and molecular processes involved in health and disease, of which inflammation represents one of the most prominent examples. Inflammation serves as a well-conserved defence mechanism, triggered in the event of chemical, mechanical or microbial damage, that is meant to eradicate the source of damage and restore tissue function. However, excessive inflammatory signals, or impairment of pro-resolving/anti-inflammatory pathways leads to chronic inflammation, which is a hallmark of chronic pathologies. All main classes of endogenous bioactive lipids - namely eicosanoids, specialized pro-resolving lipid mediators, lysoglycerophopsholipids and endocannabinoids - have been consistently involved in the chronic inflammation that characterises pathologies such as cancer, diabetes, atherosclerosis, asthma, as well as autoimmune and neurodegenerative disorders and inflammatory bowel diseases. This review gathers the current knowledge concerning the involvement of endogenous bioactive lipids in the pathogenic processes of chronic inflammatory pathologies.
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28
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The Impact of Marijuana on the Cardiovascular System: A Review of the Most Common Cardiovascular Events Associated with Marijuana Use. J Clin Med 2020; 9:jcm9061925. [PMID: 32575540 PMCID: PMC7355963 DOI: 10.3390/jcm9061925] [Citation(s) in RCA: 69] [Impact Index Per Article: 13.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/24/2020] [Revised: 06/01/2020] [Accepted: 06/16/2020] [Indexed: 02/03/2023] Open
Abstract
With the expanded legalization of marijuana, its medical and recreational use have sharply increased over the past decade. A wide array of new forms of cannabis is available on the market today, and the potencies are ten times those of forms previously tested, meaning that the true impact of marijuana on the cardiovascular system remains unclear. Cannabis mainly exerts its effects via the sympathetic and parasympathetic nervous systems, with different doses affecting different cannabinoids receptors. Studies have shown that marijuana plays a role in thrombosis, inflammation, and atherosclerosis. Case reports have linked marijuana use to myocardial infarction, cardiac arrythmias, cardiomyopathies, stroke, and arteritis. Most patients are young, healthy men with no cardiovascular risk factors; however, the patient population is expected to change to include older individuals in the future. The widespread public perception of safety accompanying marijuana use has contributed to its increased use among the elderly, who are the most at risk population for acute cardiovascular events. In this review, we aim to provide a basic understanding of the physiological effects of marijuana on the cardiovascular system and to review the current literature regarding cardiovascular diseases linked to marijuana use in adults.
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29
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Piscitelli F, Silvestri C. Role of the Endocannabinoidome in Human and Mouse Atherosclerosis. Curr Pharm Des 2020; 25:3147-3164. [PMID: 31448709 DOI: 10.2174/1381612825666190826162735] [Citation(s) in RCA: 7] [Impact Index Per Article: 1.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/19/2019] [Accepted: 08/21/2019] [Indexed: 12/20/2022]
Abstract
The Endocannabinoid (eCB) system and its role in many physiological and pathological conditions is well described and accepted, and includes cardiovascular disorders. However, the eCB system has been expanded to an "-ome"; the endocannabinoidome (eCBome) that includes endocannabinoid-related mediators, their protein targets and metabolic enzymes, many of which significantly impact upon cardiometabolic health. These recent discoveries are here summarized with a special focus on their potential involvement in atherosclerosis. We described the role of classical components of the eCB system (eCBs, CB1 and CB2 receptors) and eCB-related lipids, their regulatory enzymes and molecular targets in atherosclerosis. Furthermore, since increasing evidence points to significant cross-talk between the eCBome and the gut microbiome and the gut microbiome and atherosclerosis, we explore the possibility that a gut microbiome - eCBome axis has potential implications in atherosclerosis.
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Affiliation(s)
- Fabiana Piscitelli
- Institute of Biomolecular Chemistry, National Council of Research, Pozzuoli (NA), Italy
| | - Cristoforo Silvestri
- Institut universitaire de cardiologie et de pneumologie de Québec (IUCPQ), 2725 Chemin Sainte-Foy, Québec, QC, G1V 4G5, Canada.,Department of Medicine, Faculty of Medicine, Laval University, Quebec City, QC, Canada
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30
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Saleh-Ghadimi S, Alizadeh M, Jafari-Vayghan H, Darabi M, Golmohammadi A, Kheirouri S. Effect of flaxseed oil supplementation on the erythrocyte membrane fatty acid composition and endocannabinoid system modulation in patients with coronary artery disease: a double-blind randomized controlled trial. GENES AND NUTRITION 2020; 15:9. [PMID: 32370762 PMCID: PMC7201600 DOI: 10.1186/s12263-020-00665-1] [Citation(s) in RCA: 8] [Impact Index Per Article: 1.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Received: 08/30/2019] [Accepted: 03/05/2020] [Indexed: 01/09/2023]
Abstract
Background The endocannabinoid system (ECS) overactivation, associated with increased inflammatory process, may act as a risk factor for coronary artery disease (CAD). Dietary fat may influence the ECS tone. The aim of the present study was to investigate the effect of flaxseed oil on the erythrocyte membrane fatty acid profile and ECS activity by the measurement of serum N-arachydonoil ethanolamine (AEA) and cannabinoid receptor type-1 (CB1), cannabinoid receptor type-2 (CB2), and fatty acid amide hydrolase (FAAH) mRNA expression. Methods This clinical trial was performed on 44 patients with CAD. The intervention group received 1.5% fat milk supplemented with flaxseed oil (containing 2.5 g α-linolenic acid or ALA), while the placebo group received 1.5% fat milk for 10 weeks. The fatty acid profile of erythrocyte membrane phospholipids was measured by gas chromatography. The AEA level was determined using an ELISA kit, and real-time PCR was performed to measure CB1, CB2, and FAAH mRNA expression pre- and post-intervention. Results Flaxseed oil supplementation resulted in a significant increase in the ALA content and a significant reduction in linoleic acid (LA) content of membrane phospholipids, compared to the placebo group (MD = − 0.35 and 2.89, respectively; P < 0.05). The within group analysis showed that flaxseed oil supplementation caused a significant reduction in both LA and arachidonic acid (MD = − 4.84 and − 4.03, respectively; P < 0.05) and an elevation in the ALA (MD = 0.37, P < 0.001) content of membrane phospholipids compared with the baseline. In the intervention group, a marked reduction was observed in the serum AEA level after 10 weeks of intervention, compared with the placebo group (MD = 0.64, P = 0.016). Changes in CB2 mRNA expression in the flaxseed oil group were significant (fold change = 1.30, P = 0.003), compared with the placebo group. Conclusion Flaxseed oil supplementation could attenuate the ECS tone by decreasing the AEA level and increasing CB2 mRNA expression. Therefore, flaxseed oil may be considered a promising agent with cardioprotective properties.
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Affiliation(s)
- Sevda Saleh-Ghadimi
- Student Research Committee, Tabriz University of Medical Sciences, Tabriz, Iran
| | - Mohammad Alizadeh
- Department of Clinical Nutrition, Faculty of Nutrition and Food Sciences, Tabriz University of Medical Sciences, Tabriz, Iran.
| | | | - Masoud Darabi
- Department of Biochemistry and Clinical Laboratories, Faculty of Medicine, Tabriz University of Medical Sciences, Tabriz, Iran
| | - Ali Golmohammadi
- Cardiovascular Research Centre, Tabriz University of Medical Sciences, Tabriz, Iran
| | - Sorayya Kheirouri
- Nutrition Research Center, Tabriz University of Medical Sciences, Tabriz, Iran.
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Abstract
PURPOSE OF REVIEW The endocannabinoid system affects several physiological functions. A family of endocannabinoid receptors is susceptible to cannabis constituents. Cannabis is widely used in our society and following its recent legalization in Canada, we focus on how exposure to cannabis and pharmacologic cannabinoid receptor type 1 (CB1) inhibition affect lipoprotein levels. RECENT FINDINGS Several groups have reported that exposure to cannabis does not increase weight despite the marked increase in caloric intake. In observational studies, the effect of smoked cannabis exposure on plasma lipids is variable. Some studies in specific patient populations with longer exposure to cannabis seemed to identify slightly more favorable lipoprotein profiles in the exposed group. Several larger controlled clinical trials using orally administered rimonabant, a CB1 receptor antagonist, have consistently shown relative improvements in weight and plasma levels of triglyceride and high-density lipoprotein cholesterol among patients receiving the treatment. SUMMARY The widely variable findings on the relationship of cannabis in various forms with plasma lipids preclude any definitive conclusions. Cannabis has complex effects on the cardiovascular system and its effects on lipid profile must be considered in this overall context. Further properly controlled research is required to better understand this topic.
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Affiliation(s)
- Julieta Lazarte
- Department of Biochemistry, Schulich School of Medicine and Dentistry, Western University
- Robarts Research Institute, Schulich School of Medicine and Dentistry, Western University
- Department of Medicine, Schulich School of Medicine and Dentistry, Western University, London, Ontario, Canada
| | - Robert A Hegele
- Department of Biochemistry, Schulich School of Medicine and Dentistry, Western University
- Robarts Research Institute, Schulich School of Medicine and Dentistry, Western University
- Department of Medicine, Schulich School of Medicine and Dentistry, Western University, London, Ontario, Canada
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Clark TM, Jones JM, Hall AG, Tabner SA, Kmiec RL. Theoretical Explanation for Reduced Body Mass Index and Obesity Rates in Cannabis Users. Cannabis Cannabinoid Res 2018; 3:259-271. [PMID: 30671538 PMCID: PMC6340377 DOI: 10.1089/can.2018.0045] [Citation(s) in RCA: 49] [Impact Index Per Article: 7.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/14/2022] Open
Abstract
Introduction: Obesity is treatment-resistant, and is linked with a number of serious, chronic diseases. Adult obesity rates in the United States have tripled since the early 1960s. Recent reviews show that an increased ratio of omega-6 to omega-3 fatty acids contributes to obesity rates by increasing levels of the endocannabinoid signals AEA and 2-AG, overstimulating CB1R and leading to increased caloric intake, reduced metabolic rates, and weight gain. Cannabis, or THC, also stimulates CB1R and increases caloric intake during acute exposures. Goals: To establish the relationship between Cannabis use and body mass index, and to provide a theoretical explanation for this relationship. Results: The present meta-analysis reveals significantly reduced body mass index and rates of obesity in Cannabis users, in conjunction with increased caloric intake. Theoretical explanation: We provide for the first time a causative explanation for this paradox, in which rapid and long-lasting downregulation of CB1R following acute Cannabis consumption reduces energy storage and increases metabolic rates, thus reversing the impact on body mass index of elevated dietary omega-6/omega-3 ratios.
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Affiliation(s)
- Thomas M Clark
- Department of Biological Sciences, Indiana University South Bend, South Bend, Indiana
| | - Jessica M Jones
- Department of Biological Sciences, Indiana University South Bend, South Bend, Indiana
| | - Alexis G Hall
- Department of Biological Sciences, Indiana University South Bend, South Bend, Indiana
| | - Sara A Tabner
- Department of Biological Sciences, Indiana University South Bend, South Bend, Indiana
| | - Rebecca L Kmiec
- Department of Biological Sciences, Indiana University South Bend, South Bend, Indiana
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Moludi J, Alizadeh M, Lotfi Yagin N, Pasdar Y, Nachvak SM, Abdollahzad H, Sadeghpour Tabaei A. New insights on atherosclerosis: A cross-talk between endocannabinoid systems with gut microbiota. J Cardiovasc Thorac Res 2018; 10:129-137. [PMID: 30386532 PMCID: PMC6203867 DOI: 10.15171/jcvtr.2018.21] [Citation(s) in RCA: 20] [Impact Index Per Article: 2.9] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/14/2017] [Accepted: 09/16/2018] [Indexed: 12/22/2022] Open
Abstract
The incidence of atherosclerosis is increasing rapidly all over the world. Inflammatory processes have outstanding role in coronary artery disease (CAD) etiology and other atherosclerosis manifestations. Recently attentions have been increased about gut microbiota in many fields of medicine especially in inflammatory diseases like atherosclerosis. Ineffectiveness in gut barrier functions and subsequent metabolic endotoxemia (caused by rise in plasma lipopolysaccharide levels) is associated with low-grade chronic inflammation i.e. a recognized feature of atherosclerosis. Furthermore, the role of trimethylamine-N-oxide (TMAO), a gut bacterial metabolite has been suggested in atherosclerosis development. On the other hand, the effectiveness of gut microbiota modulation that results in TMAO reduction has been investigated. Moreover, considerable evidence supports a role for the endocannabinoid system (ECS) in atherosclerosis pathology which affects gut microbiota, but their effects on atherosclerosis are controversial. Therefore, we presented some evidence about the relationship between gut microbiota and ECS in atherosclerosis. We also presented evidences that gut microbiota modulation by pre/probiotics can have significant influence on the ECS.
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Affiliation(s)
- Jalal Moludi
- Nutrition Research Center, Faculty of Nutrition, Tabriz University of Medical Sciences, Tabriz, Iran
- Students’ Research Committee, Tabriz University of Medical Sciences, Tabriz, Iran
| | - Mohammad Alizadeh
- Nutrition Research Center, Faculty of Nutrition, Tabriz University of Medical Sciences, Tabriz, Iran
| | - Ned Lotfi Yagin
- Nutrition Research Center, Faculty of Nutrition, Tabriz University of Medical Sciences, Tabriz, Iran
| | - Yahiya Pasdar
- Nutritional Sciences Department, School of Nutritional Sciences and Food Technology, Kermanshah University of Medical Sciences, Kermanshah, Iran
| | - Seyed Mostafa Nachvak
- Nutritional Sciences Department, School of Nutritional Sciences and Food Technology, Kermanshah University of Medical Sciences, Kermanshah, Iran
| | - Hadi Abdollahzad
- Nutritional Sciences Department, School of Nutritional Sciences and Food Technology, Kermanshah University of Medical Sciences, Kermanshah, Iran
| | - Ali Sadeghpour Tabaei
- Rajaie Cardiovascular Medical and Research Center, Iran University of Medical Sciences, Tehran
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Affiliation(s)
- Naghum Alfulaij
- Laboratory of Experimental Medicine, Department of Cell and Molecular Biology, John A. Burns School of Medicine, University of Hawaii, Honolulu, HI
| | - Franziska Meiners
- Laboratory of Experimental Medicine, Department of Cell and Molecular Biology, John A. Burns School of Medicine, University of Hawaii, Honolulu, HI
| | - Justin Michalek
- Laboratory of Experimental Medicine, Department of Cell and Molecular Biology, John A. Burns School of Medicine, University of Hawaii, Honolulu, HI
- Molecular Biosciences and Bioengineering, University of Hawaii, Honolulu, HI
| | | | - Helen C Turner
- Laboratory of Immunology and Signal Transduction, Division of Natural Sciences and Mathematics, Chaminade University, Honolulu, HI
| | - Alexander J Stokes
- Laboratory of Experimental Medicine, Department of Cell and Molecular Biology, John A. Burns School of Medicine, University of Hawaii, Honolulu, HI
- Laboratory of Immunology and Signal Transduction, Division of Natural Sciences and Mathematics, Chaminade University, Honolulu, HI
- Molecular Biosciences and Bioengineering, University of Hawaii, Honolulu, HI
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Paloczi J, Varga ZV, Hasko G, Pacher P. Neuroprotection in Oxidative Stress-Related Neurodegenerative Diseases: Role of Endocannabinoid System Modulation. Antioxid Redox Signal 2018; 29:75-108. [PMID: 28497982 PMCID: PMC5984569 DOI: 10.1089/ars.2017.7144] [Citation(s) in RCA: 79] [Impact Index Per Article: 11.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 05/01/2017] [Accepted: 05/11/2017] [Indexed: 12/19/2022]
Abstract
SIGNIFICANCE Redox imbalance may lead to overproduction of reactive oxygen and nitrogen species (ROS/RNS) and subsequent oxidative tissue damage, which is a critical event in the course of neurodegenerative diseases. It is still not fully elucidated, however, whether oxidative stress is the primary trigger or a consequence in the process of neurodegeneration. Recent Advances: Increasing evidence suggests that oxidative stress is involved in the propagation of neuronal injury and consequent inflammatory response, which in concert promote development of pathological alterations characteristic of most common neurodegenerative diseases. CRITICAL ISSUES Accumulating recent evidence also suggests that there is an important interplay between the lipid endocannabinoid system [ECS; comprising the main cannabinoid 1 and 2 receptors (CB1 and CB2), endocannabinoids, and their synthetic and metabolizing enzymes] and various key inflammatory and redox-dependent processes. FUTURE DIRECTIONS Targeting the ECS to modulate redox state-dependent cell death and to decrease consequent or preceding inflammatory response holds therapeutic potential in a multitude of oxidative stress-related acute or chronic neurodegenerative disorders from stroke and traumatic brain injury to Alzheimer's and Parkinson's diseases and multiple sclerosis, just to name a few, which will be discussed in this overview. Antioxid. Redox Signal. 29, 75-108.
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Affiliation(s)
- Janos Paloczi
- Laboratory of Cardiovascular Physiology and Tissue Injury (LCPTI), National Institute on Alcohol Abuse and Alcoholism (NIAAA), National Institutes of Health (NIH), Bethesda, Maryland
| | - Zoltan V. Varga
- Laboratory of Cardiovascular Physiology and Tissue Injury (LCPTI), National Institute on Alcohol Abuse and Alcoholism (NIAAA), National Institutes of Health (NIH), Bethesda, Maryland
| | - George Hasko
- Department of Surgery, Rutgers New Jersey Medical School, Newark, New Jersey
| | - Pal Pacher
- Laboratory of Cardiovascular Physiology and Tissue Injury (LCPTI), National Institute on Alcohol Abuse and Alcoholism (NIAAA), National Institutes of Health (NIH), Bethesda, Maryland
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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; 15:151-166. [PMID: 28905873 DOI: 10.1038/nrcardio.2017.130] [Citation(s) in RCA: 283] [Impact Index Per Article: 40.4] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 12/20/2022]
Abstract
Dysregulation of the endogenous lipid mediators endocannabinoids and their G-protein-coupled cannabinoid receptors 1 and 2 (CB1R and CB2R) has been implicated in a variety of cardiovascular pathologies. Activation of CB1R facilitates the development of cardiometabolic disease, whereas activation of CB2R (expressed primarily in immune cells) exerts anti-inflammatory effects. The psychoactive constituent of marijuana, Δ9-tetrahydrocannabinol (THC), is an agonist of both CB1R and CB2R, and exerts its psychoactive and adverse cardiovascular effects through the activation of CB1R in the central nervous and cardiovascular systems. The past decade has seen a nearly tenfold increase in the THC content of marijuana as well as the increased availability of highly potent synthetic cannabinoids for recreational use. These changes have been accompanied by the emergence of serious adverse cardiovascular events, including myocardial infarction, cardiomyopathy, arrhythmias, stroke, and cardiac arrest. In this Review, we summarize the role of the endocannabinoid system in cardiovascular disease, and critically discuss the cardiovascular consequences of marijuana and synthetic cannabinoid use. With the legalization of marijuana for medicinal purposes and/or recreational use in many countries, physicians should be alert to the possibility that the use of marijuana or its potent synthetic analogues might be the underlying cause of severe cardiovascular events and pathologies.
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Affiliation(s)
- Pal Pacher
- Laboratory of Cardiovascular Physiology and Tissue Injury, National Institutes of Health/NIAAA, 5625 Fishers Lane, Bethesda, Maryland 20892, USA
| | - Sabine Steffens
- Institute for Cardiovascular Prevention, Ludwig-Maximilians-University and German Centre for Cardiovascular Research (DZHK), partner site Munich Heart Alliance, Pettenkoferstrasse 8a und 9b, Munich, D-80336, Germany
| | - György Haskó
- Department of Surgery, Rutgers New Jersey Medical School, 185 South Orange Avenue, Newark, New Jersey 07103, USA
| | - Thomas H Schindler
- Department of Radiology, Johns Hopkins University, 601 North Caroline Street, Baltimore, Maryland 21287, USA
| | - George Kunos
- Laboratory of Physiological Studies, National Institutes of Health/NIAAA, 5625 Fishers Lane, Bethesda, Maryland 20892, USA
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Peripheral modulation of the endocannabinoid system in metabolic disease. Drug Discov Today 2018; 23:592-604. [PMID: 29331500 DOI: 10.1016/j.drudis.2018.01.029] [Citation(s) in RCA: 31] [Impact Index Per Article: 4.4] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/27/2017] [Revised: 11/17/2017] [Accepted: 01/05/2018] [Indexed: 12/14/2022]
Abstract
Dysfunction of the endocannabinoid system (ECS) has been identified in metabolic disease. Cannabinoid receptor 1 (CB1) is abundantly expressed in the brain but also expressed in the periphery. Cannabinoid receptor 2 (CB2) is more abundant in the periphery, including the immune cells. In obesity, global antagonism of overexpressed CB1 reduces bodyweight but leads to centrally mediated adverse psychological outcomes. Emerging research in isolated cultured cells or tissues has demonstrated that targeting the endocannabinoid system in the periphery alleviates the pathologies associated with metabolic disease. Further, peripheral specific cannabinoid ligands can reverse aspects of the metabolic phenotype. This Keynote review will focus on current research on the functionality of peripheral modulation of the ECS for the treatment of obesity.
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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 2017; 28:35-52. [PMID: 29222605 DOI: 10.1007/s10286-017-0488-5] [Citation(s) in RCA: 41] [Impact Index Per Article: 5.1] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/19/2017] [Accepted: 11/28/2017] [Indexed: 12/18/2022]
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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Affiliation(s)
- Salvador Sierra
- Department of Pharmacological Sciences, Icahn School of Medicine at Mount Sinai, New York, NY, USA. .,Department of Physiology and Biophysics, Molecular Medicine Research Building, Virginia Commonwealth University, 1220 East Broad Street, Richmond, VA, 23298, USA.
| | - Natasha Luquin
- Department of Medical Genomics, Royal Prince Alfred Hospital, Sydney, Australia
| | - Judith Navarro-Otano
- Neurology Service, Electromyography, Motor Control and Neuropathic Pain Unit, Hospital Clínic de Barcelona, University of Barcelona, Barcelona, Spain
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Moore CF, Schlain GS, Mancino S, Sabino V, Cottone P. A behavioral and pharmacological characterization of palatable diet alternation in mice. Pharmacol Biochem Behav 2017; 163:1-8. [PMID: 29097161 PMCID: PMC5911178 DOI: 10.1016/j.pbb.2017.10.013] [Citation(s) in RCA: 12] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 09/13/2017] [Revised: 10/09/2017] [Accepted: 10/29/2017] [Indexed: 12/28/2022]
Abstract
Obesity and eating disorders are widespread in Western societies. Both the increased availability of highly palatable foods and dieting are major risk factors contributing to the epidemic of disorders of feeding. The purpose of this study was to characterize an animal model of maladaptive feeding induced by intermittent access to a palatable diet alternation in mice. In this study, mice were either continuously provided with standard chow food (Chow/Chow), or provided with standard chow for 2days and a high-sucrose, palatable food for 1day (Chow/Palatable). Following stability of intake within the cycling paradigm, we then investigated the effects of several pharmacological treatments on excessive eating of palatable food: naltrexone, an opioid receptor antagonist, SR141716A, a cannabinoid-1 receptor antagonist/inverse agonist, and BD-1063, a sigma-1 receptor antagonist. Over successive cycles, Chow/Palatable mice showed an escalation of palatable food intake within the first hour of renewed access to palatable diet and displayed hypophagia upon its removal. Naltrexone, SR141716A, and BD-1063 all reduced overconsumption of palatable food during this first hour. Here we provide evidence of strong face and convergent validity in a palatable diet alternation model in mice, confirming multiple shared underlying mechanisms of pathological eating across species, and thus making it a useful therapeutic development tool.
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Affiliation(s)
- Catherine F Moore
- Laboratory of Addictive Disorders, Departments of Pharmacology and Experimental Therapeutics and Psychiatry, Boston University School of Medicine, Boston, MA, USA; Graduate Program for Neuroscience, Boston University School of Medicine, Boston, MA, USA
| | - Gabrielle S Schlain
- Laboratory of Addictive Disorders, Departments of Pharmacology and Experimental Therapeutics and Psychiatry, Boston University School of Medicine, Boston, MA, USA
| | - Samantha Mancino
- Laboratory of Addictive Disorders, Departments of Pharmacology and Experimental Therapeutics and Psychiatry, Boston University School of Medicine, Boston, MA, USA
| | - Valentina Sabino
- Laboratory of Addictive Disorders, Departments of Pharmacology and Experimental Therapeutics and Psychiatry, Boston University School of Medicine, Boston, MA, USA
| | - Pietro Cottone
- Laboratory of Addictive Disorders, Departments of Pharmacology and Experimental Therapeutics and Psychiatry, Boston University School of Medicine, Boston, MA, USA.
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Qi H, Yang S, Zhang L. Neutrophil Extracellular Traps and Endothelial Dysfunction in Atherosclerosis and Thrombosis. Front Immunol 2017; 8:928. [PMID: 28824648 PMCID: PMC5545592 DOI: 10.3389/fimmu.2017.00928] [Citation(s) in RCA: 131] [Impact Index Per Article: 16.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/08/2017] [Accepted: 07/20/2017] [Indexed: 12/23/2022] Open
Abstract
Cardiovascular diseases are a leading cause of mortality and morbidity worldwide. Neutrophils are a component of the innate immune system which protect against pathogen invasion; however, the contribution of neutrophils to cardiovascular disease has been underestimated, despite infiltration of leukocyte subsets being a known driving force of atherosclerosis and thrombosis. In addition to their function as phagocytes, neutrophils can release their extracellular chromatin, nuclear protein, and serine proteases to form net-like fiber structures, termed neutrophil extracellular traps (NETs). NETs can entrap pathogens, induce endothelial activation, and trigger coagulation, and have been detected in atherosclerotic and thrombotic lesions in both humans and mice. Moreover, NETs can induce endothelial dysfunction and trigger proinflammatory immune responses. Overall, current data indicate that NETs are not only present in plaques and thrombi but also have causative roles in triggering formation of atherosclerotic plaques and venous thrombi. This review is focused on published findings regarding NET-associated endothelial dysfunction during atherosclerosis, atherothrombosis, and venous thrombosis pathogenesis. The NET structure is a novel discovery that will find its appropriate place in our new understanding of cardiovascular disease. In addition, NETs have high potential to be further explored toward much better treatment of atherosclerosis and venous thromboembolism in clinic.
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Affiliation(s)
- Haozhe Qi
- Department of Vascular Surgery, Renji Hospital, School of Medicine, Shanghai Jiao Tong University, Shanghai, China
| | - Shuofei Yang
- Department of Vascular Surgery, Renji Hospital, School of Medicine, Shanghai Jiao Tong University, Shanghai, China
| | - Lan Zhang
- Department of Vascular Surgery, Renji Hospital, School of Medicine, Shanghai Jiao Tong University, Shanghai, China
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Ho WSV, Kelly MEM. Cannabinoids in the Cardiovascular System. ADVANCES IN PHARMACOLOGY (SAN DIEGO, CALIF.) 2017; 80:329-366. [PMID: 28826540 DOI: 10.1016/bs.apha.2017.05.002] [Citation(s) in RCA: 25] [Impact Index Per Article: 3.1] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 02/06/2023]
Abstract
Cannabinoids are known to modulate cardiovascular functions including heart rate, vascular tone, and blood pressure in humans and animal models. Essential components of the endocannabinoid system, namely, the production, degradation, and signaling pathways of endocannabinoids have been described not only in the central and peripheral nervous system but also in myocardium, vasculature, platelets, and immune cells. The mechanisms of cardiovascular responses to endocannabinoids are often complex and may involve cannabinoid CB1 and CB2 receptors or non-CB1/2 receptor targets. Preclinical and some clinical studies have suggested that targeting the endocannabinoid system can improve cardiovascular functions in a number of pathophysiological conditions, including hypertension, metabolic syndrome, sepsis, and atherosclerosis. In this chapter, we summarize the local and systemic cardiovascular effects of cannabinoids and highlight our current knowledge regarding the therapeutic potential of endocannabinoid signaling and modulation.
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Affiliation(s)
- Wing S V Ho
- Vascular Biology Research Centre, St George's University of London, London, United Kingdom.
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Katsimpoulas M, Kadoglou NE, Moustardas P, Kapelouzou A, Dede E, Kostomitsopoulos N, Karayannacos PE, Kostakis A, Liapis CD. The role of exercise training and the endocannabinoid system in atherosclerotic plaque burden and composition in Apo-E-deficient mice. Hellenic J Cardiol 2017; 57:417-425. [PMID: 28254386 DOI: 10.1016/j.hjc.2016.11.013] [Citation(s) in RCA: 7] [Impact Index Per Article: 0.9] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/25/2015] [Accepted: 09/01/2016] [Indexed: 01/19/2023] Open
Abstract
INTRODUCTION We investigated the effect of combining exercise training and treatment with an endocannabinoid receptor 1 inhibitor (Rimonabant) on atherosclerosis burden and composition. METHODS Forty-eight apolipoprotein E-deficient (ApoE-/-) mice were kept on a 16-week high-fat diet. Mice were then placed on a normal diet and were randomized to the following groups with n=12 mice for 6 more weeks: 1) Control (Co) - no intervention; 2) Exercise (Ex) - exercise training on treadmill; 3) Rimonabant (Ri) - oral administration of rimonabant (10 mg/kg/day); or 4) Rimonabant+Exercise (RiEx) - combination of Ri and Ex groups treatment. At the end, all animals were sacrificed, and blood samples, as well as aortic root specimens, were obtained for histomorphometric analysis and quantification of the serum and plaque content of matrix metalloproteinases (MMPs). RESULTS The mean plaque area was significantly smaller (RiEx: 43.18±1.72%, Ri: 44.66±3.1%, Ex: 49±4.10%, Co: 70.43±2.83%) in all active treatment groups relative to the Co group (p<0.01). Conversely, the relative concentrations of collagen and elastin were increased significantly across all treatment groups compared to Co (p<0.05). Immunohistochemical analysis revealed significantly reduced macrophage content within plaques after all interventions, with the most pronounced effect observed after combined treatment (RiEx: 9.4±3.92%, Ri: 15±2.45%, Ex: 19.78±2.79%, Co: 34.25±4.99%; p<0.05). Within plaques, the TIMP-1 concentration was significantly upregulated in exercise-treated groups. MMP-3 and MMP-9 concentrations were equivalently decreased in all three active treatment groups compared to controls (p<0.001). DISCUSSION Both exercise and rimonabant treatments induced plaque regression and promoted plaque stability. The combined treatment failed to show additive or synergistic benefits relative to either intervention alone.
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Affiliation(s)
- Michalis Katsimpoulas
- Department of Vascular Surgery, Medical School, University of Athens, Greece; Center of Clinical, Experimental Surgery and Translational Research, Biomedical Research Foundation, Academy of Athens, Greece.
| | - Nikolaos E Kadoglou
- Department of Vascular Surgery, Medical School, University of Athens, Greece; Center of Clinical, Experimental Surgery and Translational Research, Biomedical Research Foundation, Academy of Athens, Greece
| | - Petros Moustardas
- Department of Vascular Surgery, Medical School, University of Athens, Greece; Center of Clinical, Experimental Surgery and Translational Research, Biomedical Research Foundation, Academy of Athens, Greece
| | - Alkistis Kapelouzou
- Center of Clinical, Experimental Surgery and Translational Research, Biomedical Research Foundation, Academy of Athens, Greece
| | - Eleni Dede
- Center of Clinical, Experimental Surgery and Translational Research, Biomedical Research Foundation, Academy of Athens, Greece
| | - Nikolaos Kostomitsopoulos
- Center of Clinical, Experimental Surgery and Translational Research, Biomedical Research Foundation, Academy of Athens, Greece
| | - Panayotis E Karayannacos
- Center of Clinical, Experimental Surgery and Translational Research, Biomedical Research Foundation, Academy of Athens, Greece
| | - Alkiviadis Kostakis
- Center of Clinical, Experimental Surgery and Translational Research, Biomedical Research Foundation, Academy of Athens, Greece
| | - Christos D Liapis
- Department of Vascular Surgery, Medical School, University of Athens, Greece
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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. [PMID: 28213089 DOI: 10.1016/j.pharmthera.2017.02.033] [Citation(s) in RCA: 110] [Impact Index Per Article: 13.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 02/07/2023]
Abstract
Monoglyerides (MGs) are short-lived, intermediary lipids deriving from the degradation of phospho- and neutral lipids, and monoglyceride lipase (MGL), also designated as monoacylglycerol lipase (MAGL), is the major enzyme catalyzing the hydrolysis of MGs into glycerol and fatty acids. This distinct function enables MGL to regulate a number of physiological and pathophysiological processes since both MGs and fatty acids can act as signaling lipids or precursors thereof. The most prominent MG species acting as signaling lipid is 2-arachidonoyl glycerol (2-AG) which is the most abundant endogenous agonist of cannabinoid receptors in the body. Importantly, recent observations demonstrate that 2-AG represents a quantitatively important source for arachidonic acid, the precursor of prostaglandins and other inflammatory mediators. Accordingly, MGL-mediated 2-AG degradation affects lipid signaling by cannabinoid receptor-dependent and independent mechanisms. Recent genetic and pharmacological studies gave important insights into MGL's role in (patho-)physiological processes, and the enzyme is now considered as a promising drug target for a number of disorders including cancer, neurodegenerative and inflammatory diseases. This review summarizes the basics of MG (2-AG) metabolism and provides an overview on the therapeutic potential of MGL.
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Affiliation(s)
- Gernot F Grabner
- Institute of Molecular Biosciences, University of Graz, Graz, Austria
| | - Robert Zimmermann
- Institute of Molecular Biosciences, University of Graz, Graz, Austria; BioTechMed Graz, Graz, Austria
| | - Rudolf Schicho
- Institute of Experimental and Clinical Pharmacology, Medical University of Graz, Graz, Austria; BioTechMed Graz, Graz, Austria.
| | - Ulrike Taschler
- Institute of Molecular Biosciences, University of Graz, Graz, Austria
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Dobovišek L, Hojnik M, Ferk P. 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). Int J Mol Med 2016; 38:1642-1651. [PMID: 27779654 DOI: 10.3892/ijmm.2016.2779] [Citation(s) in RCA: 28] [Impact Index Per Article: 3.1] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/26/2016] [Accepted: 10/12/2016] [Indexed: 11/06/2022] Open
Abstract
The physiological and pathophysiological roles of sex hormones have been well documented and the modulation of their effects is applicable in many current treatments. On the other hand, the physiological role of endocannabinoids is not yet clearly understood and the endocannabinoid system is considered a relatively new therapeutic target. The physiological association between sex hormones and cannabinoids has been investigated in several studies; however, its involvement in the pathophysiology of common human diseases has been studied separately. Herein, we present the first systematic review of molecular pathways that are influenced by both the cannabinoids and sex hormones, including adenylate cyclase and protein kinase A, epidermal growth factor receptor, cyclic adenosine monophosphate response element-binding protein, vascular endothelial growth factor, proto-oncogene serine/threonine-protein kinase, mitogen-activated protein kinase, phosphatidylinositol-4,5-bisphosphate 3-kinase, C-Jun N-terminal kinase and extracellular-signal-regulated kinases 1/2. Most of these influence cell proliferative activity. Better insight into this association may prove to be beneficial for the development of novel pharmacological treatment strategies for many common diseases, including breast cancer, endometrial cancer, prostate cancer, osteoporosis and atherosclerosis. The associations between cannabinoids, estrogens and androgens under these conditions are also presented and the molecular interactions are highlighted.
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Affiliation(s)
- Luka Dobovišek
- Department of Pharmacology and Experimental Toxicology, Faculty of Medicine, University of Maribor, SI-2000 Maribor, Slovenia
| | - Marko Hojnik
- Department of Pharmacology and Experimental Toxicology, Faculty of Medicine, University of Maribor, SI-2000 Maribor, Slovenia
| | - Polonca Ferk
- Department of Pharmacology and Experimental Toxicology, Faculty of Medicine, University of Maribor, SI-2000 Maribor, Slovenia
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Jehle J, Hoyer FF, Schöne B, Pfeifer P, Schild K, Jenniches I, Bindila L, Lutz B, Lütjohann D, Zimmer A, Nickenig G. Myeloid-Specific Deletion of Diacylglycerol Lipase α Inhibits Atherogenesis in ApoE-Deficient Mice. PLoS One 2016; 11:e0146267. [PMID: 26731274 PMCID: PMC4712127 DOI: 10.1371/journal.pone.0146267] [Citation(s) in RCA: 13] [Impact Index Per Article: 1.4] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/25/2015] [Accepted: 12/15/2015] [Indexed: 11/19/2022] Open
Abstract
Background The endocannabinoid 2-arachidonoylglycerol (2-AG) is a known modulator of inflammation. Despite its high concentration in vascular tissue, the role of 2-AG in atherogenesis has not yet been examined. Methods ApoE-deficient mice were sublethally irradiated and reconstituted with bone marrow from mice with a myeloid-specific knockout of the 2-AG synthesising enzyme diacylglycerol lipase α (Dagla) or control bone marrow with an intact 2-AG biosynthesis. After a cholesterol-rich diet for 8 weeks, plaque size and plaque morphology were examined in chimeric mice. Circulating inflammatory cells were assessed by flow cytometry. Aortic tissue and plasma levels of endocannabinoids were measured using liquid chromatography-multiple reaction monitoring. Results Mice with Dagla-deficient bone marrow and circulating myeloid cells showed a significantly reduced plaque burden compared to controls. The reduction in plaque size was accompanied by a significantly diminished accumulation of both neutrophil granulocytes and macrophages in atherosclerotic lesions of Dagla-deficient mice. Moreover, CB2 expression and the amount of oxidised LDL within atherosclerotic lesions was significantly reduced. FACS analyses revealed that levels of circulating inflammatory cells were unaltered in Dagla-deficient mice. Conclusions Myeloid synthesis of the endocannabinoid 2-AG appears to promote vascular inflammation and atherogenesis. Thus, myeloid-specific disruption of 2-AG synthesis may represent a potential novel therapeutic strategy against atherosclerosis.
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Affiliation(s)
- Julian Jehle
- Klinik II für Innere Medizin, Universität Bonn, Bonn, Germany
- * E-mail:
| | - Friedrich Felix Hoyer
- Massachusetts General Hospital, Center for Systems Biology, Boston, United States of America
| | - Benedikt Schöne
- Klinik II für Innere Medizin, Universität Bonn, Bonn, Germany
| | - Philipp Pfeifer
- Klinik II für Innere Medizin, Universität Bonn, Bonn, Germany
| | | | - Imke Jenniches
- Institut für Molekulare Psychiatrie, Universität Bonn, Bonn, Germany
| | - Laura Bindila
- Institut für Physiologische Chemie, Johannes Gutenberg Universität Mainz, Mainz, Germany
| | - Beat Lutz
- Institut für Physiologische Chemie, Johannes Gutenberg Universität Mainz, Mainz, Germany
| | - Dieter Lütjohann
- Institut für Klinische Chemie und Klinische Pharmakologie, Universität Bonn, Bonn, Germany
| | - Andreas Zimmer
- Institut für Molekulare Psychiatrie, Universität Bonn, Bonn, Germany
| | - Georg Nickenig
- Klinik II für Innere Medizin, Universität Bonn, Bonn, Germany
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Abstract
The endocannabinoid system is widely distributed throughout the cardiovascular system. Endocannabinoids play a minimal role in the regulation of cardiovascular function in normal conditions, but are altered in most cardiovascular disorders. In shock, endocannabinoids released within blood mediate the associated hypotension through CB(1) activation. In hypertension, there is evidence for changes in the expression of CB(1), and CB(1) antagonism reduces blood pressure in obese hypertensive and diabetic patients. The endocannabinoid system is also upregulated in cardiac pathologies. This is likely to be cardioprotective, via CB(2) and CB(1) (lesser extent). In the vasculature, endocannabinoids cause vasorelaxation through activation of multiple target sites, inhibition of calcium channels, activation of potassium channels, NO production and the release of vasoactive substances. Changes in the expression or function of any of these pathways alter the vascular effect of endocannabinoids. Endocannabinoids have positive (CB(2)) and negative effects (CB(1)) on the progression of atherosclerosis. However, any negative effects of CB(1) may not be consequential, as chronic CB(1) antagonism in large scale human trials was not associated with significant reductions in atheroma. In neurovascular disorders such as stroke, endocannabinoids are upregulated and protective, involving activation of CB(1), CB(2), TRPV1 and PPARα. Although most of this evidence is from preclinical studies, it seems likely that cannabinoid-based therapies could be beneficial in a range of cardiovascular disorders.
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Affiliation(s)
- Saoirse Elizabeth O'Sullivan
- Faculty of Medicine and Health Sciences, Division of Medical Sciences and Graduate Entry Medicine, School of Medicine, Royal Derby Hospital Centre, University of Nottingham, Room 4107, Uttoxeter Road, Derby, DE22 3DT, UK.
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Vujic N, Schlager S, Eichmann TO, Madreiter-Sokolowski CT, Goeritzer M, Rainer S, Schauer S, Rosenberger A, Woelfler A, Doddapattar P, Zimmermann R, Hoefler G, Lass A, Graier WF, Radovic B, Kratky D. Monoglyceride lipase deficiency modulates endocannabinoid signaling and improves plaque stability in ApoE-knockout mice. Atherosclerosis 2015; 244:9-21. [PMID: 26584135 PMCID: PMC4704137 DOI: 10.1016/j.atherosclerosis.2015.10.109] [Citation(s) in RCA: 30] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 06/15/2015] [Revised: 10/27/2015] [Accepted: 10/28/2015] [Indexed: 12/25/2022]
Abstract
Background and aims Monoglyceride lipase (MGL) catalyzes the final step of lipolysis by degrading monoglyceride (MG) to glycerol and fatty acid. MGL also hydrolyzes and thereby deactivates 2-arachidonoyl glycerol (2-AG), the most abundant endocannabinoid in the mammalian system. 2-AG acts as full agonist on cannabinoid receptor type 1 (CB1R) and CB2R, which are mainly expressed in brain and immune cells, respectively. Thus, we speculated that in the absence of MGL, increased 2-AG concentrations mediate CB2R signaling in immune cells to modulate inflammatory responses, thereby affecting the development of atherosclerosis. Methods and results We generated apolipoprotein E (ApoE)/MGL double-knockout (DKO) mice and challenged them with Western-type diet for 9 weeks. Despite systemically increased 2-AG concentrations in DKO mice, CB2R-mediated signaling remains fully functional, arguing against CB2R desensitization. We found increased plaque formation in both en face aortae (1.3-fold, p = 0.028) and aortic valve sections (1.5-fold, p = 0.0010) in DKO mice. Interestingly, DKO mice also presented reduced lipid (12%, p = 0.031) and macrophage content (18%, p = 0.061), elevated intraplaque smooth muscle staining (1.4-fold, p = 0.016) and thicker fibrous caps (1.8-fold, p = 0.0032), together with a higher ratio of collagen to necrotic core area (2.5-fold, p = 0.0003) and expanded collagen content (1.6-fold, p = 0.0007), which suggest formation of less vulnerable atherosclerotic plaques. Treatment with a CB2R inverse agonist prevents these effects in DKO mice, demonstrating that the observed plaque phenotype in DKO mice originates from CB2R activation. Conclusion Loss of MGL modulates endocannabinoid signaling in CB2R-expressing cells, which concomitantly affects the pathogenesis of atherosclerosis. We conclude that despite larger lesion size loss of MGL improves atherosclerotic plaque stability. Thus, pharmacological MGL inhibition may be a novel intervention to reduce plaque rupture.
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Affiliation(s)
- Nemanja Vujic
- Institute of Molecular Biology and Biochemistry, Medical University of Graz, Graz, Austria
| | - Stefanie Schlager
- Institute of Molecular Biology and Biochemistry, Medical University of Graz, Graz, Austria
| | - Thomas O Eichmann
- Institute of Molecular Biosciences, University of Graz, Graz, Austria
| | | | - Madeleine Goeritzer
- Institute of Molecular Biology and Biochemistry, Medical University of Graz, Graz, Austria
| | - Silvia Rainer
- Institute of Molecular Biology and Biochemistry, Medical University of Graz, Graz, Austria
| | - Silvia Schauer
- Institute of Pathology, Medical University of Graz, Graz, Austria
| | | | - Albert Woelfler
- Division of Hematology, Medical University of Graz, Graz, Austria
| | - Prakash Doddapattar
- Institute of Molecular Biology and Biochemistry, Medical University of Graz, Graz, Austria
| | - Robert Zimmermann
- Institute of Molecular Biosciences, University of Graz, Graz, Austria
| | - Gerald Hoefler
- Institute of Pathology, Medical University of Graz, Graz, Austria
| | - Achim Lass
- Institute of Molecular Biosciences, University of Graz, Graz, Austria
| | - Wolfgang F Graier
- Institute of Molecular Biology and Biochemistry, Medical University of Graz, Graz, Austria
| | - Branislav Radovic
- Institute of Molecular Biology and Biochemistry, Medical University of Graz, Graz, Austria
| | - Dagmar Kratky
- Institute of Molecular Biology and Biochemistry, Medical University of Graz, Graz, Austria.
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Netherland-Van Dyke C, Rodgers W, Fulmer M, Lahr Z, Thewke D. Cannabinoid Receptor Type 2 (CB2) Dependent and Independent Effects of WIN55,212-2 on Atherosclerosis in Ldlr-null Mice. ACTA ACUST UNITED AC 2015; 3:53-63. [PMID: 26413498 DOI: 10.12970/2311-052x.2015.03.02.2] [Citation(s) in RCA: 6] [Impact Index Per Article: 0.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/31/2022]
Abstract
PURPOSE WIN55,212-2, a potent synthetic agonist of cannabinoid receptor type 1 (CB1) and cannabinoid receptor type 2 (CB2), reduces atherosclerosis in apolipoprotein E (ApoE) null mice. Although pharmacologic evidence suggests the anti-atherosclerotic effects of WIN55,212-2 are mediated via CB2, this remains to be confirmed by genetic studies. Therefore, in this study, we investigated the effects of WIN55,212-2 on development of atherosclerosis in low-density lipoprotein receptor (Ldlr) null mice with and without homozygous deletion of the CB2 gene. METHODS After 6 weeks on an atherogenic diet, groups of CB2+/+ and CB2-/- Ldlr-null mice received a daily intraperitoneal injection of WIN55,212-2 or vehicle. After two weeks, plasma lipid levels and atherosclerosis in the aortic root were quantified. RESULTS Plasma cholesterol and triglyceride levels did not differ between CB2+/+ and CB2-/- mice and WIN55,212-2 had no effect on total cholesterol levels in either genotype. However, triglyceride levels in both CB2+/+ and CB2-/- mice were significantly lowered by WIN55,212-2. The size of aortic root lesions did not differ significantly between CB2+/+ and CB2-/- mice with or without WIN55,212-2 treatment. However, WIN55,212-2 treatment significantly lowered lesional macrophage accumulation in CB2+/+ mice, and lesional smooth muscle content in both CB2+/+ and CB2-/- mice. Lesional apoptosis was also greater in CB2+/+ mice compared to CB2-/-mice, and only reduced by WIN55,212-2 in CB2+/+ mice. Collagen content and elastin fiber fragmentation were unaffected by genotype or WIN55,212-2. CONCLUSIONS WIN55,212-2 treatment does not alter lesion size in Ldlr null-mice, but does modify lesion cellularity via CB2-dependent and CB2-independent mechanisms.
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Affiliation(s)
| | - Ward Rodgers
- Department of Biomedical Sciences, Center for Inflammation, Infectious Disease and Immunity, Quillen College of Medicine, East Tennessee State University, Johnson City, TN, 37614, USA
| | - Makenzie Fulmer
- Department of Biomedical Sciences, Center for Inflammation, Infectious Disease and Immunity, Quillen College of Medicine, East Tennessee State University, Johnson City, TN, 37614, USA
| | - Zachary Lahr
- Department of Biomedical Sciences, Center for Inflammation, Infectious Disease and Immunity, Quillen College of Medicine, East Tennessee State University, Johnson City, TN, 37614, USA
| | - Douglas Thewke
- Department of Biomedical Sciences, Center for Inflammation, Infectious Disease and Immunity, Quillen College of Medicine, East Tennessee State University, Johnson City, TN, 37614, USA
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Ligand activation of cannabinoid receptors attenuates hypertrophy of neonatal rat cardiomyocytes. J Cardiovasc Pharmacol 2015; 64:420-30. [PMID: 24979612 DOI: 10.1097/fjc.0000000000000134] [Citation(s) in RCA: 26] [Impact Index Per Article: 2.6] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 01/25/2023]
Abstract
: Endocannabinoids are bioactive amides, esters, and ethers of long-chain polyunsaturated fatty acids. Evidence suggests that activation of the endocannabinoid pathway offers cardioprotection against myocardial ischemia, arrhythmias, and endothelial dysfunction of coronary arteries. As cardiac hypertrophy is a convergence point of risk factors for heart failure, we determined a role for endocannabinoids in attenuating endothelin-1-induced hypertrophy and probed the signaling pathways involved. The cannabinoid receptor ligand anandamide and its metabolically stable analog, R-methanandamide, suppressed hypertrophic indicators including cardiomyocyte enlargement and fetal gene activation (ie, the brain natriuretic peptide gene) elicited by endothelin-1 in isolated neonatal rat ventricular myocytes. The ability of R-methanandamide to suppress myocyte enlargement and fetal gene activation was mediated by CB2 and CB1 receptors, respectively. Accordingly, a CB2-selective agonist, JWH-133, prevented only myocyte enlargement but not brain natriuretic peptide gene activation. A CB1/CB2 dual agonist with limited brain penetration, CB-13, inhibited both hypertrophic indicators. CB-13 activated AMP-activated protein kinase (AMPK) and, in an AMPK-dependent manner, endothelial nitric oxide synthase (eNOS). Disruption of AMPK signaling, using compound C or short hairpinRNA knockdown, and eNOS inhibition using L-NIO abolished the antihypertrophic actions of CB-13. In conclusion, CB-13 inhibits cardiomyocyte hypertrophy through AMPK-eNOS signaling and may represent a novel therapeutic approach to cardioprotection.
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