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Zachut M, Butenko Y, Dos Santos Silva P. International Symposium on Ruminant Physiology: The involvement of the endocannabinoid system in metabolic and inflammatory responses in dairy cows during negative energy balance. J Dairy Sci 2025:S0022-0302(25)00017-7. [PMID: 39824501 DOI: 10.3168/jds.2024-25772] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/26/2024] [Accepted: 12/18/2024] [Indexed: 01/20/2025]
Abstract
The endocannabinoid system (ECS) is involved in the regulation of energy metabolism, immune function and reproduction in mammals. The ECS is consisted of the endocannabinoid (eCB) ligands, enzymes, and cannabinoid receptors. In mammals, the cannabinoid-1 receptor (CB1/CNR1) is expressed in the central nervous system and in peripheral tissues; and its activation increases anabolic processes. The cannabinoid-2 receptor (CB2/CNR2) is most highly expressed in immune cells, and its activation exerts mainly anti-inflammatory effects. Until recently, little was known about the involvement of the ECS in physiological responses in dairy cows. As peripartum dairy cows undergo vast changes in energy metabolism and immune function, processes that are regulated by the ECS, several studies characterized ECS components in transition cows. Concentrations of eCB in the adipose tissue were higher postpartum (PP), and levels of the eCB N-arachidonoylethanolamide (AEA) were increased PP compared with prepartum. Exogenous injections of AEA to transition cows may increase adipose deposition, but did not affect feed intake. In vitro models showed that bovine adipocyte metabolism was differentially affected by CB1 agonists and antagonists in nonlactating non-gestating compared with PP cows. Thus, the responses of the PP dairy cows to ECS modulations may be related to the physiological and reproductive stage of the cow. Currently, whole-body ECS activation via agonists is mostly not feasible in vivo in livestock. Alternatively, downregulation of ECS activation can be achieved by supplementation of omega-3 (n-3) fatty acids. Indeed, in vivo studies with transition cows supplemented with n-3 showed a moderate downregulation of ECS components in the blood, adipose and liver, improved systemic insulin sensitivity, but evidently reduced insulin sensitivity in the adipose tissue PP. The abundance of CB1 was lower in immune cells, and anti-inflammatory effects were found in PP cows supplemented with n-3; possibly associating ECS downregulation with immune function. The physiological impact of ECS activation is an exciting and complex area of research, that could influence the physiology of dairy cows during metabolic and inflammatory challenges. Dairy cows may be an experimental model for ECS modulations, with broader relevance to female mammals. More research is required on how selective ECS activation/downregulation in tissues could affect immune-metabolic function in dairy cows.
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Affiliation(s)
- Maya Zachut
- Department of Ruminant Science, Institute of Animal Sciences, ARO Volcani Institute, Israel.
| | - Yana Butenko
- Department of Ruminant Science, Institute of Animal Sciences, ARO Volcani Institute, Israel
| | - Priscila Dos Santos Silva
- Department of Ruminant Science, Institute of Animal Sciences, ARO Volcani Institute, Israel; Department of Animal Science, The Robert H. Smith Faculty of Agriculture, Food and Environment, The Hebrew University of Jerusalem, Rehovot, Israel
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2
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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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3
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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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Ryan M, Raby E, Whiley L, Masuda R, Lodge S, Nitschke P, Maker GL, Wist J, Holmes E, Wood FM, Nicholson JK, Fear MW, Gray N. Nonsevere Burn Induces a Prolonged Systemic Metabolic Phenotype Indicative of a Persistent Inflammatory Response Postinjury. J Proteome Res 2024; 23:2893-2907. [PMID: 38104259 PMCID: PMC11302432 DOI: 10.1021/acs.jproteome.3c00516] [Citation(s) in RCA: 2] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/16/2023] [Indexed: 12/19/2023]
Abstract
Globally, burns are a significant cause of injury that can cause substantial acute trauma as well as lead to increased incidence of chronic comorbidity and disease. To date, research has primarily focused on the systemic response to severe injury, with little in the literature reported on the impact of nonsevere injuries (<15% total burn surface area; TBSA). To elucidate the metabolic consequences of a nonsevere burn injury, longitudinal plasma was collected from adults (n = 35) who presented at hospital with a nonsevere burn injury at admission, and at 6 week follow up. A cross-sectional baseline sample was also collected from nonburn control participants (n = 14). Samples underwent multiplatform metabolic phenotyping using 1H nuclear magnetic resonance spectroscopy and liquid chromatography-mass spectrometry to quantify 112 lipoprotein and glycoprotein signatures and 852 lipid species from across 20 subclasses. Multivariate data modeling (orthogonal projections to latent structures-discriminate analysis; OPLS-DA) revealed alterations in lipoprotein and lipid metabolism when comparing the baseline control to hospital admission samples, with the phenotypic signature found to be sustained at follow up. Univariate (Mann-Whitney U) testing and OPLS-DA indicated specific increases in GlycB (p-value < 1.0e-4), low density lipoprotein-2 subfractions (variable importance in projection score; VIP > 6.83e-1) and monoacyglyceride (20:4) (p-value < 1.0e-4) and decreases in circulating anti-inflammatory high-density lipoprotein-4 subfractions (VIP > 7.75e-1), phosphatidylcholines, phosphatidylglycerols, phosphatidylinositols, and phosphatidylserines. The results indicate a persistent systemic metabolic phenotype that occurs even in cases of a nonsevere burn injury. The phenotype is indicative of an acute inflammatory profile that continues to be sustained postinjury, suggesting an impact on systems health beyond the site of injury. The phenotypes contained metabolic signatures consistent with chronic inflammatory states reported to have an elevated incidence postburn injury. Such phenotypic signatures may provide patient stratification opportunities, to identify individual responses to injury, personalize intervention strategies, and improve acute care, reducing the risk of chronic comorbidity.
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Affiliation(s)
- Monique
J. Ryan
- Australian
National Phenome Centre, Health Futures Institute, Harry Perkins Institute, Murdoch University, 5 Robin Warren Drive, Perth, Western Australia 6150, Australia
- Centre
for Computational and Systems Medicine, Health Futures Institute,
Harry Perkins Institute, Murdoch University, 5 Robin Warren Drive, Perth, Western Australia 6150, Australia
| | - Edward Raby
- Burns
Service of Western Australia, WA Department
of Health, Murdoch, Western Australia 6150, Australia
- Department
of Microbiology, PathWest Laboratory Medicine, Perth, Western Australia 6009, Australia
- Department
of Infectious Diseases, Fiona Stanley Hospital, Perth, Western Australia 6150, Australia
| | - Luke Whiley
- Australian
National Phenome Centre, Health Futures Institute, Harry Perkins Institute, Murdoch University, 5 Robin Warren Drive, Perth, Western Australia 6150, Australia
- Centre
for Computational and Systems Medicine, Health Futures Institute,
Harry Perkins Institute, Murdoch University, 5 Robin Warren Drive, Perth, Western Australia 6150, Australia
| | - Reika Masuda
- Australian
National Phenome Centre, Health Futures Institute, Harry Perkins Institute, Murdoch University, 5 Robin Warren Drive, Perth, Western Australia 6150, Australia
| | - Samantha Lodge
- Australian
National Phenome Centre, Health Futures Institute, Harry Perkins Institute, Murdoch University, 5 Robin Warren Drive, Perth, Western Australia 6150, Australia
- Centre
for Computational and Systems Medicine, Health Futures Institute,
Harry Perkins Institute, Murdoch University, 5 Robin Warren Drive, Perth, Western Australia 6150, Australia
| | - Philipp Nitschke
- Australian
National Phenome Centre, Health Futures Institute, Harry Perkins Institute, Murdoch University, 5 Robin Warren Drive, Perth, Western Australia 6150, Australia
| | - Garth L. Maker
- Australian
National Phenome Centre, Health Futures Institute, Harry Perkins Institute, Murdoch University, 5 Robin Warren Drive, Perth, Western Australia 6150, Australia
| | - Julien Wist
- Australian
National Phenome Centre, Health Futures Institute, Harry Perkins Institute, Murdoch University, 5 Robin Warren Drive, Perth, Western Australia 6150, Australia
- Centre
for Computational and Systems Medicine, Health Futures Institute,
Harry Perkins Institute, Murdoch University, 5 Robin Warren Drive, Perth, Western Australia 6150, Australia
- Chemistry
Department, Universidad del Valle, Cali 76001, Colombia
| | - Elaine Holmes
- Centre
for Computational and Systems Medicine, Health Futures Institute,
Harry Perkins Institute, Murdoch University, 5 Robin Warren Drive, Perth, Western Australia 6150, Australia
- Department
of Metabolism Digestion and Reproduction, Faculty of Medicine, Imperial College London, London SW7 2AZ, United Kingdom
| | - Fiona M. Wood
- Burns
Service of Western Australia, WA Department
of Health, Murdoch, Western Australia 6150, Australia
- Burn
Injury Research Unit, School of Biomedical Sciences, University of Western Australia, Perth, Western Australia 6009, Australia
- Fiona
Wood Foundation, Perth, Western Australia 6150, Australia
| | - Jeremy K. Nicholson
- Australian
National Phenome Centre, Health Futures Institute, Harry Perkins Institute, Murdoch University, 5 Robin Warren Drive, Perth, Western Australia 6150, Australia
- Institute
of Global Health Innovation, Imperial College
London, London SW7 2AZ, United Kingdom
| | - Mark W. Fear
- Burn
Injury Research Unit, School of Biomedical Sciences, University of Western Australia, Perth, Western Australia 6009, Australia
- Fiona
Wood Foundation, Perth, Western Australia 6150, Australia
| | - Nicola Gray
- Australian
National Phenome Centre, Health Futures Institute, Harry Perkins Institute, Murdoch University, 5 Robin Warren Drive, Perth, Western Australia 6150, Australia
- Centre
for Computational and Systems Medicine, Health Futures Institute,
Harry Perkins Institute, Murdoch University, 5 Robin Warren Drive, Perth, Western Australia 6150, Australia
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Lee K, Vanin S, Nashed M, Sarikahya MH, Laviolette SR, Natale DRC, Hardy DB. Cannabidiol Exposure During Gestation Leads to Adverse Cardiac Outcomes Early in Postnatal Life in Male Rat Offspring. Cannabis Cannabinoid Res 2024; 9:781-796. [PMID: 38358335 DOI: 10.1089/can.2023.0213] [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] [Indexed: 02/16/2024] Open
Abstract
Introduction: Studies indicate that ∼7% of pregnant individuals in North America consume cannabis in pregnancy. Pre-clinical studies have established that maternal exposure to Δ9-tetrahydrocannabinol (THC; major psychoactive component in cannabis) leads to fetal growth restriction and impaired cardiac function in offspring. However, the effects of maternal exposure to cannabidiol (CBD; major non-euphoric constituent) on cardiac outcomes in offspring remain unknown. Therefore, our objective is to investigate the functional and underlying molecular impacts in the hearts of offspring exposed to CBD in pregnancy. Methods: Pregnant Wistar rats were exposed to either 3 or 30 mg/kg CBD or vehicle control i.p. daily from gestational day 6 to term. Echocardiography was used to assess cardiac function in male and female offspring at postnatal day (PND) 21. Furthermore, quantitative polymerase chain reaction (qPCR), immunoblotting, and bulk RNA-sequencing (RNA-seq) were performed on PND21 offspring hearts. Results: Despite no differences in the heart-to-body weight ratio, both doses of CBD led to reduced cardiac function exclusively in male offspring at 3 weeks of age. Underlying this, significant alterations in the expression of the endocannabinoid system (ECS; e.g., decreased cannabinoid receptor 2) were observed. In addition, bulk RNA-seq data demonstrated transcriptional pathways significantly enriched in mitochondrial function/metabolism as well as development. Conclusion: Collectively, we demonstrated for the first time that gestational exposure to CBD, a constituent perceived as safe, leads to early sex-specific postnatal cardiac deficits and alterations in the cardiac ECS in offspring.
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Affiliation(s)
- Kendrick Lee
- Department of Physiology and Pharmacology, Schulich School of Medicine and Dentistry, Western University, London, Ontario, Canada
| | - Sebastian Vanin
- Department of Physiology and Pharmacology, Schulich School of Medicine and Dentistry, Western University, London, Ontario, Canada
| | - Mina Nashed
- Department of Anatomy and Cell Biology, Schulich School of Medicine and Dentistry, Western University, London, Ontario, Canada
| | - Mohammed Halit Sarikahya
- Department of Anatomy and Cell Biology, Schulich School of Medicine and Dentistry, Western University, London, Ontario, Canada
| | - Steven R Laviolette
- Department of Anatomy and Cell Biology, Schulich School of Medicine and Dentistry, Western University, London, Ontario, Canada
| | - David R C Natale
- Departments of Biomedical and Molecular Sciences and Obstetrics and Gynaecology, Queen's University, Kingston, Canada
| | - Daniel B Hardy
- Department of Physiology and Pharmacology, Schulich School of Medicine and Dentistry, Western University, London, Ontario, Canada
- Department of Obstetrics and Gynecology, Children's Health Research Institute, Lawson Health Research Institute, Western University, London, Ontario, Canada
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Pędzińska-Betiuk A, Schlicker E, Weresa J, Malinowska B. Re-evaluation of the cardioprotective effects of cannabinoids against ischemia-reperfusion injury according to the IMproving Preclinical Assessment of Cardioprotective Therapies (IMPACT) criteria. Front Pharmacol 2024; 15:1382995. [PMID: 38873412 PMCID: PMC11170160 DOI: 10.3389/fphar.2024.1382995] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/06/2024] [Accepted: 04/05/2024] [Indexed: 06/15/2024] Open
Abstract
Ischemic heart disease, associated with high morbidity and mortality, represents a major challenge for the development of drug-based strategies to improve its prognosis. Results of pre-clinical studies suggest that agonists of cannabinoid CB2 receptors and multitarget cannabidiol might be potential cardioprotective strategies against ischemia-reperfusion injury. The aim of our study was to re-evaluate the cardioprotective effects of cannabinoids against ischemia-reperfusion injury according to the IMproving Preclinical Assessment of Cardioprotective Therapies (IMPACT) criteria published recently by the European Union (EU) CARDIOPROTECTION COST ACTION. To meet the minimum criteria of those guidelines, experiments should be performed (i) on healthy small animals subjected to ischemia with reperfusion lasting for at least 2 hours and (ii) confirmed in small animals with comorbidities and co-medications and (iii) in large animals. Our analysis revealed that the publications regarding cardioprotective effects of CB2 receptor agonists and cannabidiol did not meet all three strict steps of IMPACT. Thus, additional experiments are needed to confirm the cardioprotective activities of (endo)cannabinoids mainly on small animals with comorbidities and on large animals. Moreover, our publication underlines the significance of the IMPACT criteria for a proper planning of preclinical experiments regarding cardiac ischemia-reperfusion injury.
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Affiliation(s)
- Anna Pędzińska-Betiuk
- Department of Experimental Physiology and Pathophysiology, Medical University of Bialystok, Bialystok, Poland
| | - Eberhard Schlicker
- Department of Pharmacology and Toxicology, University of Bonn, Bonn, Germany
| | - Jolanta Weresa
- Department of Experimental Physiology and Pathophysiology, Medical University of Bialystok, Bialystok, Poland
| | - Barbara Malinowska
- Department of Experimental Physiology and Pathophysiology, Medical University of Bialystok, Bialystok, Poland
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7
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More SA, Deore RS, Pawar HD, Sharma C, Nakhate KT, Rathod SS, Ojha S, Goyal SN. CB2 Cannabinoid Receptor as a Potential Target in Myocardial Infarction: Exploration of Molecular Pathogenesis and Therapeutic Strategies. Int J Mol Sci 2024; 25:1683. [PMID: 38338960 PMCID: PMC10855244 DOI: 10.3390/ijms25031683] [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: 12/31/2023] [Revised: 01/22/2024] [Accepted: 01/25/2024] [Indexed: 02/12/2024] Open
Abstract
The lipid endocannabinoid system has recently emerged as a novel therapeutic target for several inflammatory and tissue-damaging diseases, including those affecting the cardiovascular system. The primary targets of cannabinoids are cannabinoid type 1 (CB1) and 2 (CB2) receptors. The CB2 receptor is expressed in the cardiomyocytes. While the pathological changes in the myocardium upregulate the CB2 receptor, genetic deletion of the receptor aggravates the changes. The CB2 receptor plays a crucial role in attenuating the advancement of myocardial infarction (MI)-associated pathological changes in the myocardium. Activation of CB2 receptors exerts cardioprotection in MI via numerous molecular pathways. For instance, delta-9-tetrahydrocannabinol attenuated the progression of MI via modulation of the CB2 receptor-dependent anti-inflammatory mechanisms, including suppression of pro-inflammatory cytokines like IL-6, TNF-α, and IL-1β. Through similar mechanisms, natural and synthetic CB2 receptor ligands repair myocardial tissue damage. This review aims to offer an in-depth discussion on the ameliorative potential of CB2 receptors in myocardial injuries induced by a variety of pathogenic mechanisms. Further, the modulation of autophagy, TGF-β/Smad3 signaling, MPTP opening, and ROS production are discussed. The molecular correlation of CB2 receptors with cardiac injury markers, such as troponin I, LDH1, and CK-MB, is explored. Special attention has been paid to novel insights into the potential therapeutic implications of CB2 receptor activation in MI.
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Affiliation(s)
- Sagar A. More
- Department of Pharmacology, Shri Vile Parle Kelavani Mandal’s Institute of Pharmacy, Dhule 424001, Maharashtra, India; (S.A.M.); (R.S.D.); (H.D.P.); (K.T.N.); (S.S.R.)
| | - Rucha S. Deore
- Department of Pharmacology, Shri Vile Parle Kelavani Mandal’s Institute of Pharmacy, Dhule 424001, Maharashtra, India; (S.A.M.); (R.S.D.); (H.D.P.); (K.T.N.); (S.S.R.)
| | - Harshal D. Pawar
- Department of Pharmacology, Shri Vile Parle Kelavani Mandal’s Institute of Pharmacy, Dhule 424001, Maharashtra, India; (S.A.M.); (R.S.D.); (H.D.P.); (K.T.N.); (S.S.R.)
| | - Charu Sharma
- Department of Internal Medicine, College of Medicine and Health Sciences, United Arab Emirates University, Al Ain P.O. Box 15551, United Arab Emirates;
| | - Kartik T. Nakhate
- Department of Pharmacology, Shri Vile Parle Kelavani Mandal’s Institute of Pharmacy, Dhule 424001, Maharashtra, India; (S.A.M.); (R.S.D.); (H.D.P.); (K.T.N.); (S.S.R.)
| | - Sumit S. Rathod
- Department of Pharmacology, Shri Vile Parle Kelavani Mandal’s Institute of Pharmacy, Dhule 424001, Maharashtra, India; (S.A.M.); (R.S.D.); (H.D.P.); (K.T.N.); (S.S.R.)
| | - Shreesh Ojha
- Department of Pharmacology and Therapeutics, College of Medicine and Health Sciences, United Arab Emirates University, Al Ain P.O. Box 15551, United Arab Emirates
| | - Sameer N. Goyal
- Department of Pharmacology, Shri Vile Parle Kelavani Mandal’s Institute of Pharmacy, Dhule 424001, Maharashtra, India; (S.A.M.); (R.S.D.); (H.D.P.); (K.T.N.); (S.S.R.)
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8
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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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9
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Toczek M, Ryszkiewicz P, Remiszewski P, Schlicker E, Krzyżewska A, Kozłowska H, Malinowska B. Weak Hypotensive Effect of Chronic Administration of the Dual FAAH/MAGL Inhibitor JZL195 in Spontaneously Hypertensive Rats as Revealed by Area under the Curve Analysis. Int J Mol Sci 2023; 24:10942. [PMID: 37446125 DOI: 10.3390/ijms241310942] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/28/2023] [Revised: 06/15/2023] [Accepted: 06/28/2023] [Indexed: 07/15/2023] Open
Abstract
The enhancement of the endocannabinoid tone might have a beneficial influence on hypertension. Polypharmacology proposes multi-target-directed ligands (MTDLs) as potential therapeutic agents for the treatment of complex diseases. In the present paper, we studied JZL195, a dual inhibitor of the two major endocannabinoid-degrading enzymes, fatty acid amide hydrolase (FAAH) and monoacylglycerol lipase (MAGL), in spontaneously hypertensive rats (SHR) and normotensive Wistar Kyoto rats (WKY). Hemodynamic parameters were assessed in conscious animals via radiotelemetry and tail-cuff methods and then evaluated by the area under the curve (AUC). Single administration of JZL195 induced dose-dependent weak hypotensive and bradycardic responses in SHR but not in WKY. Similarly, its chronic application revealed only a slight hypotensive potential which, however, effectively prevented the progression of hypertension and did not undergo tolerance. In addition, multiple JZL195 administrations slightly decreased heart rate only in WKY and prevented the gradual weight gain in both groups. JZL195 did not affect organ weights, blood glucose level, rectal temperature and plasma oxidative stress markers. In conclusion, chronic dual FAAH/MAGL inhibition prevents the progression of hypertension in SHR without affecting some basal functions of the body. In addition, our study clearly proves the suitability of AUC for the evaluation of weak blood pressure changes.
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Affiliation(s)
- Marek Toczek
- Department of Experimental Physiology and Pathophysiology, Medical University of Białystok, Mickiewicza Str. 2A, 15-222 Białystok, Poland
| | - Piotr Ryszkiewicz
- Department of Experimental Physiology and Pathophysiology, Medical University of Białystok, Mickiewicza Str. 2A, 15-222 Białystok, Poland
| | - Patryk Remiszewski
- Department of Experimental Physiology and Pathophysiology, Medical University of Białystok, Mickiewicza Str. 2A, 15-222 Białystok, Poland
| | - Eberhard Schlicker
- Department of Pharmacology and Toxicology, University of Bonn, Venusberg-Campus 1, 53127 Bonn, Germany
| | - Anna Krzyżewska
- Department of Experimental Physiology and Pathophysiology, Medical University of Białystok, Mickiewicza Str. 2A, 15-222 Białystok, Poland
| | - Hanna Kozłowska
- Department of Experimental Physiology and Pathophysiology, Medical University of Białystok, Mickiewicza Str. 2A, 15-222 Białystok, Poland
| | - Barbara Malinowska
- Department of Experimental Physiology and Pathophysiology, Medical University of Białystok, Mickiewicza Str. 2A, 15-222 Białystok, Poland
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10
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Dziemitko S, Harasim-Symbor E, Chabowski A. How do phytocannabinoids affect cardiovascular health? An update on the most common cardiovascular diseases. Ther Adv Chronic Dis 2023; 14:20406223221143239. [PMID: 36636553 PMCID: PMC9830002 DOI: 10.1177/20406223221143239] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/17/2022] [Accepted: 11/17/2022] [Indexed: 01/09/2023] Open
Abstract
Cardiovascular disease (CVD) causes millions of deaths worldwide each year. Despite the great progress in therapies available for patients with CVD, some limitations, including drug complications, still exist. Hence, the endocannabinoid system (ECS) was proposed as a new avenue for CVDs treatment. The ECS components are widely distributed through the body, including the heart and blood vessels, thus the action of its endogenous and exogenous ligands, in particular, phytocannabinoids play a key role in various pathological states. The cardiovascular action of cannabinoids is complex as they affect vasculature and myocardium directly via specific receptors and exert indirect effects through the central and peripheral nervous system. The growing interest in phytocannabinoid studies, however, has extended the knowledge about their molecular targets as well as therapeutical properties; nonetheless, some areas of their actions are not yet fully recognized. Researchers have reported various cannabinoids, especially cannabidiol, as a promising approach to CVDs; hence, the purpose of this review is to summarize and update the cardiovascular actions of the most potent phytocannabinoids and the potential therapeutic role of ECS in CVDs, including ischemic reperfusion injury, arrhythmia, heart failure as well as hypertension.
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Affiliation(s)
- Sylwia Dziemitko
- Department of Physiology, Medical University of
Bialystok, Bialystok 15-222, Poland
| | - Ewa Harasim-Symbor
- Department of Physiology, Medical University of
Bialystok, Bialystok, Poland
| | - Adrian Chabowski
- Department of Physiology, Medical University of
Bialystok, Bialystok, Poland
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11
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Mensah E, Tabrizchi R, Daneshtalab N. Pharmacognosy and Effects of Cannabinoids in the Vascular System. ACS Pharmacol Transl Sci 2022; 5:1034-1049. [PMID: 36407955 PMCID: PMC9667477 DOI: 10.1021/acsptsci.2c00141] [Citation(s) in RCA: 3] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/14/2022] [Indexed: 11/29/2022]
Abstract
Understanding the pharmacodynamics of cannabinoids is an essential subject due to the recent increasing global acceptance of cannabis and its derivation for recreational and therapeutic purposes. Elucidating the interaction between cannabinoids and the vascular system is critical to exploring cannabinoids as a prospective therapeutic agent for treating vascular-associated clinical conditions. This review aims to examine the effect of cannabinoids on the vascular system and further discuss the fundamental pharmacological properties and mechanisms of action of cannabinoids in the vascular system. Data from literature revealed a substantial interaction between endocannabinoids, phytocannabinoids, and synthetic cannabinoids within the vasculature of both humans and animal models. However, the mechanisms and the ensuing functional response is blood vessels and species-dependent. The current understanding of classical cannabinoid receptor subtypes and the recently discovered atypical cannabinoid receptors and the development of new synthetic analogs have further enhanced the pharmacological characterization of the vascular cannabinoid receptors. Compelling evidence also suggest that cannabinoids represent a formidable therapeutic candidate for vascular-associated conditions. Nonetheless, explanations of the mechanisms underlining these processes are complex and paradoxical based on the heterogeneity of receptors and signaling pathways. Further insight from studies that uncover the mechanisms underlining the therapeutic effect of cannabinoids in the treatment of vascular-associated conditions is required to determine whether the known benefits of cannabinoids thus currently outweigh the known/unknown risks.
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Affiliation(s)
- Eric Mensah
- Faculty
of Medicine, Division of Biomedical Sciences, Memorial University of Newfoundland and Labrador, St. John’s, NL A1C 5S7, Canada
| | - Reza Tabrizchi
- Faculty
of Medicine, Division of Biomedical Sciences, Memorial University of Newfoundland and Labrador, St. John’s, NL A1C 5S7, Canada
| | - Noriko Daneshtalab
- School
of Pharmacy, Memorial University of Newfoundland
and Labrador, St. John’s, NL A1B 3V6, Canada
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12
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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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13
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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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14
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Why Do Marijuana and Synthetic Cannabimimetics Induce Acute Myocardial Infarction in Healthy Young People? Cells 2022; 11:cells11071142. [PMID: 35406706 PMCID: PMC8997492 DOI: 10.3390/cells11071142] [Citation(s) in RCA: 22] [Impact Index Per Article: 7.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/04/2022] [Revised: 03/18/2022] [Accepted: 03/23/2022] [Indexed: 12/19/2022] Open
Abstract
The use of cannabis preparations has steadily increased. Although cannabis was traditionally assumed to only have mild vegetative side effects, it has become evident in recent years that severe cardiovascular complications can occur. Cannabis use has recently even been added to the risk factors for myocardial infarction. This review is dedicated to pathogenetic factors contributing to cannabis-related myocardial infarction. Tachycardia is highly important in this respect, and we provide evidence that activation of CB1 receptors in brain regions important for cardiovascular regulation and of presynaptic CB1 receptors on sympathetic and/or parasympathetic nerve fibers are involved. The prototypical factors for myocardial infarction, i.e., thrombus formation and coronary constriction, have also been considered, but there is little evidence that they play a decisive role. On the other hand, an increase in the formation of carboxyhemoglobin, impaired mitochondrial respiration, cardiotoxic reactions and tachyarrhythmias associated with the increased sympathetic tone are factors possibly intensifying myocardial infarction. A particularly important factor is that cannabis use is frequently accompanied by tobacco smoking. In conclusion, additional research is warranted to decipher the mechanisms involved, since cannabis use is being legalized increasingly and Δ9-tetrahydrocannabinol and its synthetic analogue nabilone are indicated for the treatment of various disease states.
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15
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Weresa J, Pędzińska-Betiuk A, Schlicker E, Hirnle G, Mitrosz M, Malinowska B. Beneficial and harmful effects of CB 1 and CB 2 receptor antagonists on chronotropic and inotropic effects related to atrial β-adrenoceptor activation in humans and in rats with primary hypertension. Clin Exp Pharmacol Physiol 2021; 48:1547-1557. [PMID: 34333780 DOI: 10.1111/1440-1681.13560] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/20/2021] [Revised: 07/22/2021] [Accepted: 07/29/2021] [Indexed: 11/26/2022]
Abstract
We have previously shown that cannabinoid CB1 and CB2 receptor antagonists, AM251 and AM630, respectively, modulate cardiostimulatory effects of isoprenaline in atria of Wistar rats. The aim of the present study was to examine whether such modulatory effects can also be observed (a) in the human atrium and (b) in spontaneously hypertensive rats (SHR) and normotensive Wistar Kyoto rats (WKY). Inotropic effects of isoprenaline and/or CGP12177 (that activate the high- and low-affinity site of β1 -adrenoceptors, respectively) were examined in paced human atrial trabeculae and rat left atria; chronotropic effects were studied in spontaneously beating right rat atria. AM251 modified cardiostimulatory effects more strongly than AM630. Therefore, AM251 (1 μM) enhanced the chronotropic effect of isoprenaline in WKY and SHR as well as inotropic action of isoprenaline in WKY and in human atria. It also increased the inotropic influence of CGP12177 in SHR. AM630 (1 μM) decreased the inotropic effect of isoprenaline and CGP12177 in WKY, but enhanced the isoprenaline-induced inotropic effect in SHR and human atria. Furthermore, AM251 (0.1 and 3 μM) and AM630 (0.1 μM) reduced the inotropic action of isoprenaline in human atria. In conclusion, cannabinoid receptor antagonists have potentially harmful and beneficial effects through their amplificatory effects on β-adrenoceptor-mediated positive chronotropic and inotropic actions, respectively.
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MESH Headings
- Animals
- Humans
- Rats
- Receptor, Cannabinoid, CB1/antagonists & inhibitors
- Receptor, Cannabinoid, CB1/metabolism
- Male
- Rats, Inbred SHR
- Heart Atria/drug effects
- Heart Atria/metabolism
- Heart Atria/physiopathology
- Receptor, Cannabinoid, CB2/antagonists & inhibitors
- Receptor, Cannabinoid, CB2/metabolism
- Isoproterenol/pharmacology
- Hypertension/physiopathology
- Hypertension/drug therapy
- Hypertension/metabolism
- Hypertension/chemically induced
- Piperidines/pharmacology
- Myocardial Contraction/drug effects
- Heart Rate/drug effects
- Pyrazoles/pharmacology
- Rats, Inbred WKY
- Receptors, Adrenergic, beta/metabolism
- Indoles/pharmacology
- Cannabinoid Receptor Antagonists/pharmacology
- Female
- Propanolamines
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Affiliation(s)
- Jolanta Weresa
- Department of Experimental Physiology and Pathophysiology, Medical University of Białystok, Białystok, Poland
| | - Anna Pędzińska-Betiuk
- Department of Experimental Physiology and Pathophysiology, Medical University of Białystok, Białystok, Poland
| | - Eberhard Schlicker
- Department of Pharmacology and Toxicology, University of Bonn, Bonn, Germany
| | - Grzegorz Hirnle
- Department of Cardiac Surgery, Medical University of Białystok, Białystok, Poland
| | - Maciej Mitrosz
- Department of Cardiac Surgery, Medical University of Białystok, Białystok, Poland
| | - Barbara Malinowska
- Department of Experimental Physiology and Pathophysiology, Medical University of Białystok, Białystok, Poland
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16
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Meeran MFN, Laham F, Azimullah S, Sharma C, Al Kaabi AJ, Tariq S, Adeghate E, Goyal SN, Ojha S. β-Caryophyllene, a natural bicyclic sesquiterpene attenuates β-adrenergic agonist-induced myocardial injury in a cannabinoid receptor-2 dependent and independent manner. Free Radic Biol Med 2021; 167:348-366. [PMID: 33588052 DOI: 10.1016/j.freeradbiomed.2021.01.046] [Citation(s) in RCA: 19] [Impact Index Per Article: 4.8] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 10/25/2019] [Revised: 12/26/2020] [Accepted: 01/25/2021] [Indexed: 12/11/2022]
Abstract
The downregulation of cannabinoid type-2 receptors (CB2R) have been reported in numerous diseases including cardiovascular diseases (CVDs). The activation of CB2R has recently emerged as an important therapeutic target to mitigate myocardial injury. We examined whether CB2R activation can protect against isoproterenol (ISO)-induced myocardial injury (MI) in rats. In the present study, we investigated the cardioprotective effect of β-caryophyllene (BCP), a naturally occurring dietary cannabinoid in rat model of MI. Rats were pre- and co-treated with BCP (50 mg/kg, orally) twice daily for 10 days along with subcutaneous injection of ISO (85 mg/kg) at an interval of 24 h for two days (9th and 10th days). AM630 (1 mg/kg), a CB2 receptor antagonist, was injected intraperitoneal as a pharmacological challenge prior to BCP treatment to reveal CB2R-mediated cardioprotective mechanisms of BCP. Desensitization of beta-adrenergic receptor (β-AR) signaling, receptor phosphorylation and recruitment of adapter β-arrestins were observed in ISO-induced MI in rats. ISO injections caused impaired cardiac function, elevated the levels of serum cardiac marker enzymes, and enhanced oxidative stress markers along with altered PI3K/Akt and NrF2/Keap1/HO-1 signaling pathways. ISO also promoted lysosomal dysfunction along with activation of NLRP3 inflammasomes and TLR4-NFκB/MAPK signaling and triggered rise in proinflammatory cytokines. There was a concomitant mitochondrial dysfunction followed by the activation of endoplasmic reticulum (ER) stress-mediated Hippo signaling and intrinsic pathway of apoptosis as well as altered autophagic flux/mTOR signaling in ISO-induced MI. Furthermore, ISO also triggered dyslipidemia evidenced by altered lipids, lipoproteins and lipid marker enzymes along with ionic homeostasis malfunction. However, treatment with BCP resulted in significant protective effects on all biochemical and molecular parameters analyzed. The cardioprotective effects were further strengthened by preservation of cardiomyocytes and cell organelles as observed in histopathological and ultrastructural studies. Interestingly, treatment with AM630, a CB2R antagonist was observed to abrogate the protective effects of BCP on the biochemical and molecular parameters except hyperlipidemia and ionic homeostasis in ISO-induced MI in rats. The present study findings demonstrate that BCP possess the potential to protect myocardium against ISO-induced MI in a CB2-dependent and independent manner.
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Affiliation(s)
- M F Nagoor Meeran
- Department of Pharmacology and Therapeutics, College of Medicine and Health Sciences, United Arab Emirates University, PO Box - 17666, Al Ain, United Arab Emirates
| | - Farah Laham
- Department of Pharmacology and Therapeutics, College of Medicine and Health Sciences, United Arab Emirates University, PO Box - 17666, Al Ain, United Arab Emirates
| | - Sheikh Azimullah
- Department of Pharmacology and Therapeutics, College of Medicine and Health Sciences, United Arab Emirates University, PO Box - 17666, Al Ain, United Arab Emirates
| | - Charu Sharma
- Department of Internal Medicine, College of Medicine and Health Sciences, United Arab Emirates University, PO Box - 17666, Al Ain, United Arab Emirates
| | - Ahmed Juma Al Kaabi
- Department of Pharmacology and Therapeutics, College of Medicine and Health Sciences, United Arab Emirates University, PO Box - 17666, Al Ain, United Arab Emirates
| | - Saeed Tariq
- Department of Anatomy, College of Medicine and Health Sciences, United Arab Emirates University, PO Box - 17666, Al Ain, United Arab Emirates
| | - Ernest Adeghate
- Department of Anatomy, College of Medicine and Health Sciences, United Arab Emirates University, PO Box - 17666, Al Ain, United Arab Emirates
| | - Sameer N Goyal
- Shri Vile Parle Kelavani Mandal's Institute of Pharmacy, Dhule, 424001, Maharashtra, India
| | - Shreesh Ojha
- Department of Pharmacology and Therapeutics, College of Medicine and Health Sciences, United Arab Emirates University, PO Box - 17666, Al Ain, United Arab Emirates.
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17
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2-arachidonoylglycerol might be a novel therapeutic target in the treatment of cardiovascular disease. Int J Cardiol 2021; 332:162. [PMID: 33811959 DOI: 10.1016/j.ijcard.2021.03.075] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 03/20/2021] [Accepted: 03/29/2021] [Indexed: 11/20/2022]
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18
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Shaffer BL, Davis GM, Incitti MA, Piper BJ, Entler BV. Application of medical cannabis in unstable angina and coronary artery disease: A case report. Medicine (Baltimore) 2021; 100:e25172. [PMID: 33726006 PMCID: PMC7982176 DOI: 10.1097/md.0000000000025172] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 11/24/2020] [Accepted: 02/04/2021] [Indexed: 01/05/2023] Open
Abstract
RATIONALE First discovered in 1990, the endocannabinoid system (ECS) was initially shown to have an intimate relationship with central areas of the nervous system associated with pain, reward, and motivation. Recently, however, the ECS has been extensively implicated in the cardiovascular system with contractility, heart rate, blood pressure, and vasodilation. Emerging data demonstrate modulation of the ECS plays an essential role in cardio metabolic risk, atherosclerosis, and can even limit damage to cardiomyocytes during ischemic events. PATIENT CONCERNS This case describes a 63-year-old man who presented to a primary care physician for a medical cannabis (MC) consult due to unstable angina (UA) not relieved by morphine or cardiac medications; having failed all first- and second-line polypharmaceutical therapies. The patient reported frequent, unprovoked, angina and exertional dyspnea. DIAGNOSIS Having a complex cardiac history, the patient first presented 22 years ago after a suspected myocardial infarction. He re-presented in 2010 and underwent stent placement at that time for inoperable triple-vessel coronary artery disease (CAD) which was identified via percutaneous transluminal coronary angioplasty. UA developed on follow-up and, despite medical management over the past 6 years, became progressively debilitating. INTERVENTIONS AND OUTCOMES In conjunction with his standard cardiac care, patient had a gradual lessening of UA-related pain, including frequency and character, after using an edible form of MC (1:1 cannabidiol:Δ9-tetrahydrocannabinol). Following continued treatment, he ceased long-term morphine treatment and described the pain as no longer crippling. As demonstrated by his exercise tolerance tests, the patient experienced an improved functional capacity and reported an increase in his daily functioning, and overall activity. LESSONS This case uniquely highlights MC in possibly reducing the character, quality, and frequency of UA, whereas concordantly improving functional cardiac capacity in a patient with CAD. Additional case reports are necessary to verify this.
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Affiliation(s)
| | | | | | - Brian J. Piper
- Geisinger Commonwealth School of Medicine, Scranton
- Center for Pharmacy Innovation and Outcomes, Forty Fort, PA
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19
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Karimian Azari E, Kerrigan A, O’Connor A. Naturally Occurring Cannabinoids and their Role in Modulation of Cardiovascular Health. J Diet Suppl 2020; 17:625-650. [DOI: 10.1080/19390211.2020.1790708] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.6] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/12/2022]
Affiliation(s)
| | - Aileen Kerrigan
- Research and Development department, University College Dublin, Dublin, Ireland
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20
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Schloss MJ, Horckmans M, Guillamat-Prats R, Hering D, Lauer E, Lenglet S, Weber C, Thomas A, Steffens S. 2-Arachidonoylglycerol mobilizes myeloid cells and worsens heart function after acute myocardial infarction. Cardiovasc Res 2020; 115:602-613. [PMID: 30295758 DOI: 10.1093/cvr/cvy242] [Citation(s) in RCA: 31] [Impact Index Per Article: 6.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 03/07/2018] [Revised: 06/06/2018] [Accepted: 10/04/2018] [Indexed: 12/19/2022] Open
Abstract
AIMS Myocardial infarction (MI) leads to an enhanced release of endocannabinoids and a massive accumulation of neutrophils and monocytes within the ischaemic myocardium. These myeloid cells originate from haematopoietic precursors in the bone marrow and are rapidly mobilized in response to MI. We aimed to determine whether endocannabinoid signalling is involved in myeloid cell mobilization and cardiac recruitment after ischaemia onset. METHODS AND RESULTS Intravenous administration of endocannabinoid 2-arachidonoylglycerol (2-AG) into wild type (WT) C57BL6 mice induced a rapid increase of blood neutrophil and monocyte counts as measured by flow cytometry. This effect was blunted when using cannabinoid receptor 2 knockout mice. In response to MI induced in WT mice, the lipidomic analysis revealed significantly elevated plasma and cardiac levels of the endocannabinoid 2-AG 24 h after infarction, but no changes in anandamide, palmitoylethanolamide, and oleoylethanolamide. This was a consequence of an increased expression of 2-AG synthesizing enzyme diacylglycerol lipase and a decrease of metabolizing enzyme monoacylglycerol lipase (MAGL) in infarcted hearts, as determined by quantitative RT-PCR analysis. The opposite mRNA expression pattern was observed in bone marrow. Pharmacological blockade of MAGL with JZL184 and thus increased systemic 2-AG levels in WT mice subjected to MI resulted in elevated cardiac CXCL1, CXCL2, and MMP9 protein levels as well as higher cardiac neutrophil and monocyte counts 24 h after infarction compared with vehicle-treated mice. Increased post-MI inflammation in these mice led to an increased infarct size, an impaired ventricular scar formation assessed by histology and a worsened cardiac function in echocardiography evaluations up to 21 days. Likewise, JZL184-administration in a myocardial ischaemia-reperfusion model increased cardiac myeloid cell recruitment and resulted in a larger fibrotic scar size. CONCLUSION These findings suggest that changes in endocannabinoid gradients due to altered tissue levels contribute to myeloid cell recruitment from the bone marrow to the infarcted heart, with crucial consequences on cardiac healing and function.
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Affiliation(s)
- Maximilian J Schloss
- Institute for Cardiovascular Prevention (IPEK), Ludwig-Maximilians-University (LMU) Munich, Pettenkoferstr. 9, Munich, Germany
| | - Michael Horckmans
- Institute for Cardiovascular Prevention (IPEK), Ludwig-Maximilians-University (LMU) Munich, Pettenkoferstr. 9, Munich, Germany.,Institut de Recherche Interdisciplinaire en Biologie Humaine et Moléculaire (IRIBHM), Université Libre de Bruxelles (U.L.B.), Brussels, Belgium
| | - Raquel Guillamat-Prats
- Institute for Cardiovascular Prevention (IPEK), Ludwig-Maximilians-University (LMU) Munich, Pettenkoferstr. 9, Munich, Germany
| | - Daniel Hering
- Institute for Cardiovascular Prevention (IPEK), Ludwig-Maximilians-University (LMU) Munich, Pettenkoferstr. 9, Munich, Germany
| | - Estelle Lauer
- Unit of Toxicology, CURML, Lausanne University Hospital, Geneva University Hospitals, rue Michel-Servet 1, Geneva CH-1211, Switzerland
| | - Sebastien Lenglet
- Unit of Toxicology, CURML, Lausanne University Hospital, Geneva University Hospitals, rue Michel-Servet 1, Geneva CH-1211, Switzerland
| | - Christian Weber
- Institute for Cardiovascular Prevention (IPEK), Ludwig-Maximilians-University (LMU) Munich, Pettenkoferstr. 9, Munich, Germany.,Department of Biochemistry, Cardiovascular Research Institute Maastricht (CARIM), Maastricht University, Maastricht, The Netherlands.,German Centre for Cardiovascular Research (DZHK), Partner Site, Munich Heart Alliance, Munich, Germany
| | - Aurelien Thomas
- Unit of Toxicology, CURML, Lausanne University Hospital, Geneva University Hospitals, rue Michel-Servet 1, Geneva CH-1211, Switzerland.,Faculty of Biology and Medicine, University of Lausanne, Vulliette 04, Lausanne 1000, Switzerland
| | - Sabine Steffens
- Institute for Cardiovascular Prevention (IPEK), Ludwig-Maximilians-University (LMU) Munich, Pettenkoferstr. 9, Munich, Germany.,German Centre for Cardiovascular Research (DZHK), Partner Site, Munich Heart Alliance, Munich, Germany
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21
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Scharf EL, Ebbert JO. Endocannabinoids and Stroke Prevention: Review of Clinical Studies. Cannabis Cannabinoid Res 2020; 5:6-11. [PMID: 32322672 DOI: 10.1089/can.2018.0066] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/18/2022] Open
Abstract
The societal burden of ischemic stroke suggests a need for additional therapeutic categories in stroke prevention. Modulation of the endocannabinoid system (ECS) is a rational target for stroke prevention because of its effects on inflammation, vascular tone, and metabolic balance, all well-described stroke risk factors. In this article, we summarize the existing ECS clinical studies in human subjects' research as they relate to conventional vascular risk factors associated with ischemic stroke. To date, 2-arachidonoylglycerol (2-AG) derivative endocannabinoids are consistently reported to be elevated in insulin resistance, whereas the N-arachidonoylethanolamine (AEA) endocannabinoid derivatives are elevated in obesity. The ECS role in metabolic health should examine the effects of 2-AG reduction and AEA augmentation as a means of stroke risk reduction. Cannabinoid receptors are reported on macrophages within atherosclerotic plaques and suggest a role for immunomodulation as a therapeutic for atherosclerosis through both peripheral immune cell CB1 antagonism and/or CB2 agonist. The effects of ECS on hypertension, smoking, physical activity, obstructive sleep apnea, heart failure, and atrial fibrillation are incompletely described and deserve further study. A limitation to ECS research is significant overlap with noncannabinoid molecular targets. Further exploration of the ECS needs to include the larger metabolomics context for a greater understanding of its therapeutic potential. Clinical translational studies in stroke prevention should be directed at ECS in metabolic balance and atherosclerosis.
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Affiliation(s)
| | - Jon O Ebbert
- Community Internal Medicine, Mayo Clinic, Rochester, Minnesota
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22
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van Esbroeck ACM, Varga ZV, Di X, van Rooden EJ, Tóth VE, Onódi Z, Kuśmierczyk M, Leszek P, Ferdinandy P, Hankemeier T, van der Stelt M, Pacher P. Activity-based protein profiling of the human failing ischemic heart reveals alterations in hydrolase activities involving the endocannabinoid system. Pharmacol Res 2020; 151:104578. [PMID: 31794870 PMCID: PMC6980785 DOI: 10.1016/j.phrs.2019.104578] [Citation(s) in RCA: 10] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 09/14/2019] [Revised: 11/22/2019] [Accepted: 11/26/2019] [Indexed: 01/14/2023]
Abstract
AIM Acute myocardial infarction and subsequent post-infarction heart failure are among the leading causes of mortality worldwide. The endocannabinoid system has emerged as an important modulator of cardiovascular disease, however the role of endocannabinoid metabolic enzymes in heart failure is still elusive. Herein, we investigated the endocannabinoids and their metabolic enzymes in ischemic end-stage failing human hearts and non-failing controls. METHODS AND RESULTS Quantitative real-time PCR, targeted lipidomics, and activity-based protein profiling (ABPP) enabled assessment of the endocannabinoids and their metabolic enzymes in ischemic end-stage failing human hearts and non-failing controls. Based on lipidomic analysis, two subgroups were identified within the ischemic heart failure group; the first similar to control hearts and the second with decreased levels of the endocannabinoid 2-arachidonoyl-glycerol (2-AG) and drastically increased levels of the endocannabinoid anandamide (AEA), other N-acylethanolamines (NAEs) and free fatty acids. The altered lipid profile was accompanied by strong reductions in the activity of 13 hydrolases, including the 2-AG hydrolytic enzyme monoacylglycerol lipase (MGLL). CONCLUSIONS Our findings suggest the presence of different biological states within the ischemic heart failure group, based on alterations in the lipid and hydrolase activity profiles. In addition, this study demonstrates that ABPP is a valuable tool to rapidly analyze enzyme activity in clinical samples with potential for novel drug and biomarker discovery.
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Affiliation(s)
- Annelot C M van Esbroeck
- Department of Molecular Physiology, Leiden Institute of Chemistry, Leiden University, the Netherlands
| | - Zoltan V Varga
- Laboratory of Cardiovascular Physiology and Tissue Injury, National Institutes of Health/NIAAA, Bethesda, USA; Department of Pharmacology and Pharmacotherapy, Faculty of Medicine, Semmelweis University, Budapest, Hungary; HCEMM-SU Cardiometabolic Immunology Research Group, Semmelweis University, Budapest, Hungary
| | - Xinyu Di
- Department of Analytical Biosciences, Leiden Academic Centre for Drug Research, Leiden University, the Netherlands
| | - Eva J van Rooden
- Department of Molecular Physiology, Leiden Institute of Chemistry, Leiden University, the Netherlands
| | - Viktória E Tóth
- Department of Pharmacology and Pharmacotherapy, Faculty of Medicine, Semmelweis University, Budapest, Hungary; HCEMM-SU Cardiometabolic Immunology Research Group, Semmelweis University, Budapest, Hungary
| | - Zsófia Onódi
- Department of Pharmacology and Pharmacotherapy, Faculty of Medicine, Semmelweis University, Budapest, Hungary; HCEMM-SU Cardiometabolic Immunology Research Group, Semmelweis University, Budapest, Hungary
| | - Mariusz Kuśmierczyk
- Department of Heart Failure and Transplantology, Cardinal Stefan Wyszyński Institute of Cardiology, Warszawa, Poland
| | - Przemyslaw Leszek
- Department of Heart Failure and Transplantology, Cardinal Stefan Wyszyński Institute of Cardiology, Warszawa, Poland
| | - Péter Ferdinandy
- Department of Pharmacology and Pharmacotherapy, Faculty of Medicine, Semmelweis University, Budapest, Hungary; Pharmahungary Group, Szeged, Hungary
| | - Thomas Hankemeier
- Department of Analytical Biosciences, Leiden Academic Centre for Drug Research, Leiden University, the Netherlands
| | - Mario van der Stelt
- Department of Molecular Physiology, Leiden Institute of Chemistry, Leiden University, the Netherlands
| | - Pál Pacher
- Laboratory of Cardiovascular Physiology and Tissue Injury, National Institutes of Health/NIAAA, Bethesda, USA.
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Hauer D, Toth R, Schelling G. Endocannabinoids, “New-Old” Mediators of Stress Homeostasis. STRESS CHALLENGES AND IMMUNITY IN SPACE 2020:181-204. [DOI: 10.1007/978-3-030-16996-1_10] [Citation(s) in RCA: 4] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 01/03/2025]
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Puhl SL. Cannabinoid-sensitive receptors in cardiac physiology and ischaemia. BIOCHIMICA ET BIOPHYSICA ACTA-MOLECULAR CELL RESEARCH 2019; 1867:118462. [PMID: 30890410 DOI: 10.1016/j.bbamcr.2019.03.009] [Citation(s) in RCA: 36] [Impact Index Per Article: 6.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Subscribe] [Scholar Register] [Received: 11/28/2018] [Revised: 03/04/2019] [Accepted: 03/15/2019] [Indexed: 02/06/2023]
Abstract
The classical cannabinoid receptors CB1 and CB2 as well as the cannabinoid-sensitive receptor GPR55 are widely distributed throughout the mammalian body. In the cardiovascular field, CB1 and CB2 crucially impact on diseases characterized by inflammatory processes, such as atherosclerosis and acute myocardial infarction. Both receptors and their endogenous ligands anandamide and 2-arachidonoylglycerol are up-regulated in the ischaemic heart in humans and animal models. Pharmacological and genetic interventions with CB1 and CB2 vitally affect acute ischaemia-induced cardiac inflammation. Herein, CB1 rather aggravates the inflammatory response whereas CB2 mitigates inflammation via directly affecting immune cell attraction, macrophage polarization and lymphocyte clusters in the pericardial adipose tissue. Furthermore, cannabinoids and their receptors affect numerous cardiac risk factors. In this context, cannabis consumption is debated to trigger arrhythmias and even myocardial infarction. Moreover, CB1 activation is linked to impaired lipid and glucose metabolism and therefore obesity and diabetes, while its antagonism leads to the reduction of plasma triglycerides, low-density lipoprotein cholesterol, leptin, insulin and glucose. On the other hand, activation of cannabinoid-sensitive receptors can also counteract unfavourable predictors for cardiovascular diseases. In particular, hypertension can be mitigated via CB1 agonism and impaired adrenoceptor responsiveness prevented by functional GPR55. Taken together, current insights identify the cannabinoid system as promising target not only to therapeutically interfere with the vasculature, but also to affect the heart as target organ. This review discusses current knowledge regarding a direct cardiac role of the cannabinoid system and points out its feasible therapeutic manipulation in the ischaemic myocardium.
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Affiliation(s)
- Sarah-Lena Puhl
- Institute for Cardiovascular Prevention, Ludwig-Maximilians-University (LMU), Pettenkoferstrasse 9, 80336 Munich, Germany.
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25
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Kasacka I, Piotrowska Ż, Filipek A, Lebkowski W. Comparative evaluation of cannabinoid receptors, apelin and S100A6 protein in the heart of women of different age groups. BMC Cardiovasc Disord 2018; 18:190. [PMID: 30286717 PMCID: PMC6172787 DOI: 10.1186/s12872-018-0923-0] [Citation(s) in RCA: 5] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/08/2017] [Accepted: 09/18/2018] [Indexed: 12/19/2022] Open
Abstract
Background Recent studies have shown a significant role of the endocannabinoid system, apelin and S100A6 protein in the regulation of cardiovascular system functioning. The aim of the study was to compare and evaluate the distribution of cannabinoid receptors (CB1 and CB2), apelin and S100A6 protein in the heart of healthy women in different age groups. Methods The study was conducted on the hearts of 10 women (organ donors) without a history of cardiovascular disease, who were divided into two age groups: women older than 50 years and women under 50 years of age. Paraffin heart sections were processed by immunohistochemistry for detection of cannabinoids receptors (CB1 and CB2), apelin and S100A6 protein. Results CB1 and CB2 immunoreactivity in the cytoplasm of cardiomyocytes in the heart of women over 50 was weaker than in younger individuals. There was also strong immunoreactivity of CB1 in intercalated discs (ICDs) of the heart, only in women over 50. The presence of this receptor in this location was not found in women under 50. Apelin- and S100A6-immunoreactivity in the cardiomyocytes was stronger in older women compared to women under 50.The CB1, apelin and S100A6 immunostaining in the endothelium of myocardial vessels was weaker in women over 50 than in younger women, while intensity of CB2- immunoreaction in coronary endothelium was similar in both groups of women. The results of the study indicate the important role of endocannabinoids, apelin, and S100A6 protein in cardiac muscle function. Conclusion This report might contribute to a better understanding of the role of endocannabinoid system, apelin and S100 proteins in heart function as well as shed new light on processes involved in age-related cardiomyopathy.
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Affiliation(s)
- Irena Kasacka
- Department of Histology and Cytophysiology, Medical University of Bialystok, Mickiewicza 2C street, 15-222, Białystok, Poland.
| | - Żaneta Piotrowska
- Department of Histology and Cytophysiology, Medical University of Bialystok, Mickiewicza 2C street, 15-222, Białystok, Poland
| | - Anna Filipek
- Nencki Institute of Experimental Biology, Laboratory of Calcium Binding Proteins, Ludwika Pasteura 3 street, 02-093, Warszawa, Poland
| | - Wojciech Lebkowski
- Department of Neurosurgery, Medical University of Bialystok, Marii Skłodowskiej-Curie 24A street, 15-276, Białystok, Poland
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Enhanced endocannabinoid tone as a potential target of pharmacotherapy. Life Sci 2018; 204:20-45. [PMID: 29729263 DOI: 10.1016/j.lfs.2018.04.054] [Citation(s) in RCA: 72] [Impact Index Per Article: 10.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/31/2018] [Revised: 04/19/2018] [Accepted: 04/28/2018] [Indexed: 12/21/2022]
Abstract
The endocannabinoid system is up-regulated in numerous pathophysiological states such as inflammatory, neurodegenerative, gastrointestinal, metabolic and cardiovascular diseases, pain, and cancer. It has been suggested that this phenomenon primarily serves an autoprotective role in inhibiting disease progression and/or diminishing signs and symptoms. Accordingly, enhancement of endogenous endocannabinoid tone by inhibition of endocannabinoid degradation represents a promising therapeutic approach for the treatment of many diseases. Importantly, this allows for the avoidance of unwanted psychotropic side effects that accompany exogenously administered cannabinoids. The effects of endocannabinoid metabolic pathway modulation are complex, as endocannabinoids can exert their actions directly or via numerous metabolites. The two main strategies for blocking endocannabinoid degradation are inhibition of endocannabinoid-degrading enzymes and inhibition of endocannabinoid cellular uptake. To date, the most investigated compounds are inhibitors of fatty acid amide hydrolase (FAAH), an enzyme that degrades the endocannabinoid anandamide. However, application of FAAH inhibitors (and consequently other endocannabinoid degradation inhibitors) in medicine became questionable due to a lack of therapeutic efficacy in clinical trials and serious adverse effects evoked by one specific compound. In this paper, we discuss multiple pathways of endocannabinoid metabolism, changes in endocannabinoid levels across numerous human diseases and corresponding experimental models, pharmacological strategies for enhancing endocannabinoid tone and potential therapeutic applications including multi-target drugs with additional targets outside of the endocannabinoid system (cyclooxygenase-2, cholinesterase, TRPV1, and PGF2α-EA receptors), and currently used medicines or medicinal herbs that additionally enhance endocannabinoid levels. Ultimately, further clinical and preclinical studies are warranted to develop medicines for enhancing endocannabinoid tone.
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27
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Fulmer ML, Thewke DP. The Endocannabinoid System and Heart Disease: The Role of Cannabinoid Receptor Type 2. Cardiovasc Hematol Disord Drug Targets 2018; 18:34-51. [PMID: 29412125 PMCID: PMC6020134 DOI: 10.2174/1871529x18666180206161457] [Citation(s) in RCA: 41] [Impact Index Per Article: 5.9] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/11/2017] [Revised: 01/01/2018] [Accepted: 01/01/2018] [Indexed: 12/24/2022]
Abstract
Decades of research has provided evidence for the role of the endocannabinoid system in human health and disease. This versatile system, consisting of two receptors (CB1 and CB2), their endogenous ligands (endocannabinoids), and metabolic enzymes has been implicated in a wide variety of disease states, ranging from neurological disorders to cancer. CB2 has gained much interest for its beneficial immunomodulatory role that can be obtained without eliciting psychotropic effects through CB1. Recent studies have shed light on a protective role of CB2 in cardiovascular disease, an ailment which currently takes more lives each year in Western countries than any other disease or injury. By use of CB2 knockout mice and CB2-selective ligands, knowledge of how CB2 signaling affects atherosclerosis and ischemia has been acquired, providing a major stepping stone between basic science and translational clinical research. Here, we summarize the current understanding of the endocannabinoid system in human pathologies and provide a review of the results from preclinical studies examining its function in cardiovascular disease, with a particular emphasis on possible CB2-targeted therapeutic interventions to alleviate atherosclerosis.
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Affiliation(s)
- Makenzie L. Fulmer
- Department of Biomedical Sciences, Center for Inflammation, Infectious Disease and Immunity, Quillen College of Medicine, East Tennessee State University, Johnson City, TN, USA
| | - Douglas P. Thewke
- Department of Biomedical Sciences, Center for Inflammation, Infectious Disease and Immunity, Quillen College of Medicine, East Tennessee State University, Johnson City, TN, USA
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Circulating Endocannabinoids: From Whence Do They Come and Where are They Going? Neuropsychopharmacology 2018; 43:155-172. [PMID: 28653665 PMCID: PMC5719092 DOI: 10.1038/npp.2017.130] [Citation(s) in RCA: 294] [Impact Index Per Article: 42.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 04/04/2017] [Revised: 05/29/2017] [Accepted: 06/09/2017] [Indexed: 12/15/2022]
Abstract
The goal of this review is to summarize studies in which concentrations of circulating endocannabinoids in humans have been examined in relationship to physiological measurements and pathological status. The roles of endocannabinoids in the regulation of energy intake and storage have been well studied and the data obtained consistently support the hypothesis that endocannabinoid signaling is associated with increased consumption and storage of energy. Physical exercise mobilizes endocannabinoids, which could contribute to refilling of energy stores and also to the analgesic and mood-elevating effects of exercise. Circulating concentrations of 2-arachidonoylglycerol are very significantly circadian and dysregulated when sleep is disrupted. Other conditions under which circulating endocannabinoids are altered include inflammation and pain. A second important role for endocannabinoid signaling is to restore homeostasis following stress. Circulating endocannabinoids are stress-responsive and there is evidence that their concentrations are altered in disorders associated with excessive stress, including post-traumatic stress disorder. Although determination of circulating endocannabinoids can provide important information about the state of endocannabinoid signaling and thus allow for hypotheses to be defined and tested, the large number of physiological factors that contribute to their circulating concentrations makes it difficult to use them in isolation as a biomarker for a specific disorder.
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Scharf EL. Translating Endocannabinoid Biology into Clinical Practice: Cannabidiol for Stroke Prevention. Cannabis Cannabinoid Res 2017; 2:259-264. [PMID: 29098188 PMCID: PMC5665427 DOI: 10.1089/can.2017.0033] [Citation(s) in RCA: 6] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/06/2023] Open
Abstract
Introduction: The endocannabinoid system (ECS) regulates functions throughout human physiology, including neuropsychiatric, cardiovascular, autonomic, metabolic, and inflammatory states. The complex cellular interactions regulated by the ECS suggest a potential for vascular disease and stroke prevention by augmenting central nervous and immune cell endocannabinoid signaling. Discussion: The endocannabinoid N-arachidonoylethanolamine (anandamide) plays a central role in augmenting these processes in cerebrovascular and neurometabolic disease. Furthermore, cannabidiol (CBD), a nonpsychoactive constituent of Cannabis, is an immediate therapeutic candidate both for potentiating endocannabinoid signaling and for acting at multiple pharmacological targets. Conclusion: This speculative synthesis explores the current state of knowledge of the ECS and suggests CBD as a therapeutic candidate for stroke prevention by exerting favorable augmentation of the homeostatic effects of the ECS and, in turn, improving the metabolic syndrome, while simultaneously stalling the development of atherosclerosis.
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Activation of Endocannabinoid Receptor 2 as a Mechanism of Propofol Pretreatment-Induced Cardioprotection against Ischemia-Reperfusion Injury in Rats. OXIDATIVE MEDICINE AND CELLULAR LONGEVITY 2017; 2017:2186383. [PMID: 28814985 PMCID: PMC5549482 DOI: 10.1155/2017/2186383] [Citation(s) in RCA: 27] [Impact Index Per Article: 3.4] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Received: 02/11/2017] [Revised: 04/20/2017] [Accepted: 04/30/2017] [Indexed: 01/16/2023]
Abstract
Propofol pretreatment before reperfusion, or propofol conditioning, has been shown to be cardioprotective, while its mechanism is unclear. The current study investigated the roles of endocannabinoid signaling in propofol cardioprotection in an in vivo model of myocardial ischemia/reperfusion (I/R) injury and in in vitro primary cardiomyocyte hypoxia/reoxygenation (H/R) injury. The results showed that propofol conditioning increased both serum and cell culture media concentrations of endocannabinoids including anandamide (AEA) and 2-arachidonoylglycerol (2-AG) detected by LC-MS/MS. The reductions of myocardial infarct size in vivo and cardiomyocyte apoptosis and death in vitro were accompanied with attenuations of oxidative injuries manifested as decreased reactive oxygen species (ROS), malonaldehyde (MDA), and MPO (myeloperoxidase) and increased superoxide dismutase (SOD) production. These effects were mimicked by either URB597, a selective endocannabinoids degradation inhibitor, or VDM11, a selective endocannabinoids reuptake inhibitor. In vivo study further validated that the cardioprotective and antioxidative effects of propofol were reversed by selective CB2 receptor antagonist AM630 but not CB1 receptor antagonist AM251. We concluded that enhancing endogenous endocannabinoid release and subsequent activation of CB2 receptor signaling represent a major mechanism whereby propofol conditioning confers antioxidative and cardioprotective effects against myocardial I/R injury.
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Abstract
Cannabis sativa has long been used for medicinal purposes. To improve safety and efficacy, compounds from C. sativa were purified or synthesized and named under an umbrella group as cannabinoids. Currently, several cannabinoids may be prescribed in Canada for a variety of indications such as nausea and pain. More recently, an increasing number of reports suggest other salutary effects associated with endogenous cannabinoid signaling including cardioprotection. The therapeutic potential of cannabinoids is therefore extended; however, evidence is limited and mechanisms remain unclear. In addition, the use of cannabinoids clinically has been hindered due to pronounced psychoactive side effects. This review provides an overview on the endocannabinoid system, including known physiological roles, and conditions in which cannabinoid receptor signaling has been implicated.
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Affiliation(s)
- Yan Lu
- a College of Pharmacy, Rady Faculty of Health Sciences, University of Manitoba, 750 McDermot Avenue, Winnipeg, MB R3E 0T5, Canada.,b Canadian Centre for Agri-Food Research in Health and Medicine, St. Boniface Hospital Research Centre, 351 Taché Avenue, Winnipeg, MB R2H 2A6, Canada
| | - Hope D Anderson
- a College of Pharmacy, Rady Faculty of Health Sciences, University of Manitoba, 750 McDermot Avenue, Winnipeg, MB R3E 0T5, Canada.,b Canadian Centre for Agri-Food Research in Health and Medicine, St. Boniface Hospital Research Centre, 351 Taché Avenue, Winnipeg, MB R2H 2A6, Canada.,c Department of Pharmacology and Therapeutics, Max Rady College of Medicine, University of Manitoba, 753 McDermot Avenue, Winnipeg, MB R3E 0T6, Canada
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Ligresti A, De Petrocellis L, Di Marzo V. From Phytocannabinoids to Cannabinoid Receptors and Endocannabinoids: Pleiotropic Physiological and Pathological Roles Through Complex Pharmacology. Physiol Rev 2016; 96:1593-659. [DOI: 10.1152/physrev.00002.2016] [Citation(s) in RCA: 253] [Impact Index Per Article: 28.1] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/17/2022] Open
Abstract
Apart from having been used and misused for at least four millennia for, among others, recreational and medicinal purposes, the cannabis plant and its most peculiar chemical components, the plant cannabinoids (phytocannabinoids), have the merit to have led humanity to discover one of the most intriguing and pleiotropic endogenous signaling systems, the endocannabinoid system (ECS). This review article aims to describe and critically discuss, in the most comprehensive possible manner, the multifaceted aspects of 1) the pharmacology and potential impact on mammalian physiology of all major phytocannabinoids, and not only of the most famous one Δ9-tetrahydrocannabinol, and 2) the adaptive pro-homeostatic physiological, or maladaptive pathological, roles of the ECS in mammalian cells, tissues, and organs. In doing so, we have respected the chronological order of the milestones of the millennial route from medicinal/recreational cannabis to the ECS and beyond, as it is now clear that some of the early steps in this long path, which were originally neglected, are becoming important again. The emerging picture is rather complex, but still supports the belief that more important discoveries on human physiology, and new therapies, might come in the future from new knowledge in this field.
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Affiliation(s)
- Alessia Ligresti
- Endocannabinoid Research Group, Institute of Biomolecular Chemistry, Consiglio Nazionale delle Ricerche, Comprensorio Olivetti, Pozzuoli, Italy
| | - Luciano De Petrocellis
- Endocannabinoid Research Group, Institute of Biomolecular Chemistry, Consiglio Nazionale delle Ricerche, Comprensorio Olivetti, Pozzuoli, Italy
| | - Vincenzo Di Marzo
- Endocannabinoid Research Group, Institute of Biomolecular Chemistry, Consiglio Nazionale delle Ricerche, Comprensorio Olivetti, Pozzuoli, Italy
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Richardson KA, Hester AK, McLemore GL. Prenatal cannabis exposure - The "first hit" to the endocannabinoid system. Neurotoxicol Teratol 2016; 58:5-14. [PMID: 27567698 DOI: 10.1016/j.ntt.2016.08.003] [Citation(s) in RCA: 86] [Impact Index Per Article: 9.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/26/2016] [Revised: 07/25/2016] [Accepted: 08/19/2016] [Indexed: 12/18/2022]
Abstract
As more states and countries legalize medical and/or adult recreational marijuana use, the incidences of prenatal cannabis exposure (PCE) will likely increase. While young people increasingly view marijuana as innocuous, marijuana preparations have been growing in potency in recent years, potentially creating global clinical, public health, and workforce concerns. Unlike fetal alcohol spectrum disorder, there is no phenotypic syndrome associated with PCE. There is also no preponderance of evidence that PCE causes lifelong cognitive, behavioral, or functional abnormalities, and/or susceptibility to subsequent addiction. However, there is compelling circumstantial evidence, based on the principles of teratology and fetal malprogramming, suggesting that pregnant women should refrain from smoking marijuana. The usage of marijuana during pregnancy perturbs the fetal endogenous cannabinoid signaling system (ECSS), which is present and active from the early embryonic stage, modulating neurodevelopment and continuing this role into adulthood. The ECSS is present in virtually every brain structure and organ system, and there is also evidence that this system is important in the regulation of cardiovascular processes. Endocannabinoids (eCBs) undergird a broad spectrum of processes, including the early stages of fetal neurodevelopment and uterine implantation. Delta-9-tetrahydrocannabinol (THC), the psychoactive chemical in cannabis, enters maternal circulation, and readily crosses the placental membrane. THC binds to CB receptors of the fetal ECSS, altering neurodevelopment and possibly rewiring ECSS circuitry. In this review, we discuss the Double-Hit Hypothesis as it relates to PCE. We contend that PCE, similar to a neurodevelopmental teratogen, delivers the first hit to the ECSS, which is compromised in such a way that a second hit (i.e., postnatal stressors) will precipitate the emergence of a specific phenotype. In summary, we conclude that perturbations of the intrauterine milieu via the introduction of exogenous CBs alter the fetal ECSS, predisposing the offspring to abnormalities in cognition and altered emotionality. Based on recent experimental evidence that we will review here, we argue that young women who become pregnant should immediately take a "pregnant pause" from using marijuana.
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Affiliation(s)
- Kimberlei A Richardson
- Howard University College of Medicine, Department of Pharmacology, 520 W Street, NW, Suite 3408, Washington, DC 20059, United States.
| | - Allison K Hester
- Howard University College of Medicine, Department of Pharmacology, 520 W Street, NW, Suite 3408, Washington, DC 20059, United States.
| | - Gabrielle L McLemore
- Morgan State University, Department of Biology-SCMMS, 1700 East Cold Spring Lane, Baltimore, MD 21251, United States.
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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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Heinemann JC, Duerr GD, Keppel K, Breitbach M, Fleischmann BK, Zimmer A, Wehner S, Welz A, Dewald O. CB2 receptor-mediated effects of pro-inflammatory macrophages influence survival of cardiomyocytes. Life Sci 2015; 138:18-28. [DOI: 10.1016/j.lfs.2014.11.027] [Citation(s) in RCA: 16] [Impact Index Per Article: 1.6] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/28/2014] [Revised: 11/15/2014] [Accepted: 11/25/2014] [Indexed: 12/13/2022]
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Möhnle P, Schütz SV, Schmidt M, Hinske C, Hübner M, Heyn J, Beiras-Fernandez A, Kreth S. MicroRNA-665 is involved in the regulation of the expression of the cardioprotective cannabinoid receptor CB2 in patients with severe heart failure. Biochem Biophys Res Commun 2014; 451:516-21. [DOI: 10.1016/j.bbrc.2014.08.008] [Citation(s) in RCA: 24] [Impact Index Per Article: 2.2] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/29/2014] [Accepted: 08/01/2014] [Indexed: 02/05/2023]
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MicroRNA-150 inhibits expression of adiponectin receptor 2 and is a potential therapeutic target in patients with chronic heart failure. J Heart Lung Transplant 2014; 33:252-60. [DOI: 10.1016/j.healun.2013.10.014] [Citation(s) in RCA: 14] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/19/2013] [Revised: 07/14/2013] [Accepted: 10/09/2013] [Indexed: 11/20/2022] Open
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Cyclooxygenase metabolism mediates vasorelaxation to 2-arachidonoylglycerol (2-AG) in human mesenteric arteries. Pharmacol Res 2014; 81:74-82. [PMID: 24548820 PMCID: PMC3992009 DOI: 10.1016/j.phrs.2014.02.001] [Citation(s) in RCA: 22] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 05/21/2013] [Revised: 01/19/2014] [Accepted: 02/03/2014] [Indexed: 01/04/2023]
Abstract
Objective The vasorelaxant effect of 2-arachidonoylglycerol (2-AG) has been well characterised in animals. 2-AG is present in human vascular cells and is up-regulated in cardiovascular pathophysiology. However, the acute vascular actions of 2-AG have not been explored in humans. Approach Mesenteric arteries were obtained from patients receiving colorectal surgery and mounted on a myograph. Arteries were contracted and 2-AG concentration–response curves were carried out. Mechanisms of action were characterised pharmacologically. Post hoc analysis was carried out to assess the effects of cardiovascular disease/risk factors on 2-AG responses. Results 2-AG caused vasorelaxation of human mesenteric arteries, independent of cannabinoid receptor or transient receptor potential vanilloid-1 activation, the endothelium, nitric oxide or metabolism via monoacyglycerol lipase or fatty acid amide hydrolase. 2-AG-induced vasorelaxation was reduced in the presence of indomethacin and flurbiprofen, suggesting a role for cyclooxygenase metabolism 2-AG. Responses to 2-AG were also reduced in the presence of Cay10441, L-161982 and potentiated in the presence of AH6809, suggesting that metabolism of 2-AG produces both vasorelaxant and vasoconstrictor prostanoids. Finally, 2-AG-induced vasorelaxation was dependent on potassium efflux and the presence of extracellular calcium. Conclusions We have shown for the first time that 2-AG causes vasorelaxation of human mesenteric arteries. Vasorelaxation is dependent on COX metabolism, activation of prostanoid receptors (EP4 & IP) and ion channel modulation. 2-AG responses are blunted in patients with cardiovascular risk factors.
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Endocannabinoid system as a potential mechanism for n-3 long-chain polyunsaturated fatty acid mediated cardiovascular protection. Proc Nutr Soc 2013; 72:460-9. [PMID: 24020800 DOI: 10.1017/s0029665113003406] [Citation(s) in RCA: 13] [Impact Index Per Article: 1.1] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/18/2022]
Abstract
The presence of an active and functioning endocannabinoid (EC) system within cardiovascular tissues implies that this system has either a physiological or pathophysiological role (or both), and there is a substantial literature to support the notion that, in the main, they are protective in the setting of various CVD states. Moreover, there is an equally extensive literature to demonstrate the cardio- and vasculo-protective effects of n-3 long-chain (LC)-PUFA. It is now becoming evident that there appears to be a close relationship between dietary intervention with n-3 LC-PUFA and changes in tissue levels of EC, raising the question as to whether or not EC may, at least in part, play a role in mediating the cardio-and vasculo-protective effects of n-3 LC-PUFA. This brief review summarises the current understanding of how both EC and n-3 LC-PUFA exert their protective effects in three major cardiovascular disorders (hypertension, atherosclerosis and acute myocardial infarction) and attempts to identify the similarities and differences that may indicate common or integrated mechanisms. From the data available, it is unlikely that in hypertension EC mediate any beneficial effects of n-3 LC-PUFA, since they do not share common mechanisms of blood pressure reduction. However, inhibition of inflammation is an effect shared by EC and n-3 LC-PUFA in the setting of both atherosclerosis and myocardial reperfusion injury, while blockade of L-type Ca2+ channels is one of the possible common mechanisms for their antiarrhythmic effects. Although both EC and n-3 LC-PUFA demonstrate vasculo- and cardio-protection, the literature overwhelmingly shows that n-3 LC-PUFA decrease tissue levels of EC through formation of EC–n-3 LC-PUFA conjugates, which is counter-intuitive to an argument that EC may mediate the effects of n-3 LC-PUFA. However, the discovery that these conjugates have a greater affinity for cannabinoid receptors than the native EC provides a fascinating avenue for further research into novel approaches for the treatment and prevention of atherosclerosis and myocardial injury following ischaemia/reperfusion.
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Liao Y, Bin J, Luo T, Zhao H, Ledent C, Asakura M, Xu D, Takashima S, Kitakaze M. CB1 cannabinoid receptor deficiency promotes cardiac remodeling induced by pressure overload in mice. Int J Cardiol 2013; 167:1936-44. [DOI: 10.1016/j.ijcard.2012.05.033] [Citation(s) in RCA: 16] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 09/09/2011] [Revised: 03/07/2012] [Accepted: 05/04/2012] [Indexed: 02/09/2023]
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Slavic S, Lauer D, Sommerfeld M, Kemnitz UR, Grzesiak A, Trappiel M, Thöne-Reineke C, Baulmann J, Paulis L, Kappert K, Kintscher U, Unger T, Kaschina E. Cannabinoid receptor 1 inhibition improves cardiac function and remodelling after myocardial infarction and in experimental metabolic syndrome. J Mol Med (Berl) 2013; 91:811-23. [DOI: 10.1007/s00109-013-1034-0] [Citation(s) in RCA: 51] [Impact Index Per Article: 4.3] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/18/2012] [Revised: 03/13/2013] [Accepted: 03/19/2013] [Indexed: 12/27/2022]
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Pacher P, Kunos G. Modulating the endocannabinoid system in human health and disease--successes and failures. FEBS J 2013; 280:1918-1943. [PMID: 23551849 PMCID: PMC3684164 DOI: 10.1111/febs.12260] [Citation(s) in RCA: 281] [Impact Index Per Article: 23.4] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/14/2013] [Revised: 03/11/2013] [Accepted: 03/19/2013] [Indexed: 12/20/2022]
Abstract
The discovery of the endocannabinoid system, comprising the G-protein coupled cannabinoid 1 and 2 receptors (CB1/2), their endogenous lipid ligands or endocannabinoids, and synthetic and metabolizing enzymes, has triggered an avalanche of experimental studies implicating the endocannabinoid system in a growing number of physiological/pathological functions. These studies have also suggested that modulating the activity of the endocannabinoid system holds therapeutic promise for a broad range of diseases, including neurodegenerative, cardiovascular and inflammatory disorders; obesity/metabolic syndrome; cachexia; chemotherapy-induced nausea and vomiting; and tissue injury and pain, amongst others. However, clinical trials with globally acting CB1 antagonists in obesity/metabolic syndrome, and other studies with peripherally-restricted CB1/2 agonists and inhibitors of the endocannabinoid metabolizing enzyme in pain, have introduced unexpected complexities, suggesting that a better understanding of the pathophysiological role of the endocannabinoid system is required to devise clinically successful treatment strategies.
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Affiliation(s)
- Pál Pacher
- Laboratory of Physiologic Studies, National Institute on Alcohol Abuse and Alcoholism, National Institutes of Health, Bethesda, MD 20892-9413, USA.
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Duerr GD, Heinemann JC, Dunkel S, Zimmer A, Lutz B, Lerner R, Roell W, Mellert F, Probst C, Esmailzadeh B, Welz A, Dewald O. Myocardial hypertrophy is associated with inflammation and activation of endocannabinoid system in patients with aortic valve stenosis. Life Sci 2013; 92:976-83. [PMID: 23567807 DOI: 10.1016/j.lfs.2013.03.014] [Citation(s) in RCA: 26] [Impact Index Per Article: 2.2] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/01/2013] [Revised: 03/13/2013] [Accepted: 03/22/2013] [Indexed: 12/31/2022]
Abstract
AIMS Endocannabinoids and their receptors have been associated with cardiac adaptation to injury, inflammation and fibrosis. Experimental studies suggested a role for inflammatory reaction and active remodeling in myocardial hypertrophy, but they have not been shown in human hypertrophy. We investigated the association of the endocannabinoid system with myocardial hypertrophy in patients with aortic stenosis. MAIN METHODS Myocardial biopsies were collected from patients with aortic stenosis (AS) and atrial myxoma as controls during surgery. Histological and molecular analysis of endocannabinoids and their receptors, inflammatory and remodeling-related cells and mediators was performed. KEY FINDINGS Myocardial hypertrophy was confirmed with significantly higher cardiomyocyte diameter in AS than in myxoma patients, which had normal cell size. AS patients presented compensated myocardial adaptation to pressure overload. AS patients had significantly higher: concentration of endocannabinoid anandamide, expression of its degrading enzyme FAAH, and of cannabinoid receptor CB2, being predominantly located on cardiomyocytes. Cell density of macrophages and newly recruited leukocytes were higher in AS group, which together with increased expression of chemokines CCL2, CCL4 and CXCL8, and suppression of anti-inflammatory IL-10 indicates persistent inflammatory reaction. We found higher myofibroblast density and stronger tenascin C staining along with mRNA induction of tenascin C and CTGF in AS patients showing active myocardial remodeling. SIGNIFICANCE Our study shows for the first time activation of the endocannabinoid system and predominant expression of its receptor CB2 on cardiomyocytes being associated with persistent inflammation and active remodeling in hypertrophic myocardium of patients with aortic stenosis.
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Affiliation(s)
- Georg D Duerr
- Department of Cardiac Surgery, University Clinical Center Bonn, Sigmund-Freud-Str. 25, 53105 Bonn, Germany
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Steffens S, Pacher P. Targeting cannabinoid receptor CB(2) in cardiovascular disorders: promises and controversies. Br J Pharmacol 2012; 167:313-323. [PMID: 22612332 PMCID: PMC3481040 DOI: 10.1111/j.1476-5381.2012.02042.x] [Citation(s) in RCA: 91] [Impact Index Per Article: 7.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/08/2012] [Revised: 04/23/2012] [Accepted: 05/14/2012] [Indexed: 12/21/2022] Open
Abstract
Cardiovascular disease is the leading cause of death and disability worldwide, which can be largely attributed to atherosclerosis, a chronic inflammation of the arteries characterized by lesions containing immune and smooth muscle cells, lipids and extracellular matrix. In recent years, the lipid endocannabinoid system has emerged as a new therapeutic target in variety of disorders associated with inflammation and tissue injury, including those of the cardiovascular system. The discovery that Δ-9-tetrahydrocannabinol (Δ9-THC), the main active constituent of marijuana, inhibited atherosclerotic plaque progression via a cannabinoid 2 (CB(2) ) receptor-dependent anti-inflammatory mechanism, and that certain natural and synthetic cannabinoid ligands could modulate the myocardial or cerebral ischaemia-reperfusion-induced tissue damage, have stimulated impetus for a growing number of studies investigating the implication of CB(2) receptors in atherosclerosis, restenosis, stroke, myocardial infarction and heart failure. The aim of this review is to update on recent findings and controversies on the role of CB(2) receptors in cardiovascular disease. Particular emphasis will be placed on novel insights in the potential cellular targets of CB(2) stimulation in cardiovascular system (e.g. endothelial and vascular smooth muscle cells, cardiomyocytes, infiltrating and/or resident monocytes/macrophages and leukocytes, etc.), their interplay and intracellular signalling mechanisms identified, as well as on experimental and clinical studies.
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Affiliation(s)
- Sabine Steffens
- Division of Cardiology, Department of Internal Medicine, University Hospital, Foundation for Medical ResearchesGeneva, Switzerland
| | - Pál Pacher
- Section on Oxidative Stress Tissue Injury, Laboratory of Physiological Studies, National Institutes of Health, NIAAABethesda, Maryland, USA
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Cappellano G, Uberti F, Caimmi PP, Pietronave S, Mary DASG, Dianzani C, Micalizzi E, Melensi M, Boldorini R, Nicosia G, Crosio E, Chiocchetti A, Aina F, Prat M, Dianzani U, Vacca G, Ariatti C, Grossini E. Different expression and function of the endocannabinoid system in human epicardial adipose tissue in relation to heart disease. Can J Cardiol 2012; 29:499-509. [PMID: 22926037 DOI: 10.1016/j.cjca.2012.06.003] [Citation(s) in RCA: 18] [Impact Index Per Article: 1.4] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/03/2012] [Revised: 06/05/2012] [Accepted: 06/06/2012] [Indexed: 11/17/2022] Open
Abstract
BACKGROUND The endocannabinoid system reportedly plays a role in the pathogenesis of cardiovascular diseases. This system is expressed also in adipose tissue, which could thus be involved in cardiac disorders through modulation of metabolically triggered inflammation. The current study aims to determine the relevance of the endocannabinoid system in epicardial adipose tissue in heart disease. METHODS Expression of the endocannabinoid receptors CB1 and CB2, and of the endocannabinoid-degrading enzyme, fatty acid amidohydrolase, and activation of protein kinase A (PKA), phospholipase C (PLC), protein kinase C (PKC), endothelial nitric oxide synthase (eNOS) and inducible (i)NOS, and extracellular signal-regulated kinases 1 and 2 (ERK1/2) (a member of the reperfusion-injury salvage kinase pathway), were analyzed by Western blot in patients after coronary artery bypass surgery (ischemics; N = 18) or valve surgery (nonischemics; N = 15) and in preadipocytes isolated from epicardial adipose tissue. RESULTS In ischemics, the CB1-to-CB2 expression ratio shifted toward CB1 and was accompanied by higher PKA activation. In contrast, in nonischemics, CB2, fatty acid amidohydrolase, PLC and PKC, and ERK1/2 were upregulated. Moreover, NO production and iNOS-to-eNOS ratios were higher in preadipocytes from ischemics. CONCLUSIONS These results show a different modulation and functioning of the endocannabinoid system in ischemics compared with nonischemics. Hence, while CB2, PLC and PKC, ERK1/2, and eNOS are more strongly expressed in patients without ischemic heart disease, high CB1 and PKA expression is associated with low survival intracellular pathway activation and high iNOS activation in ischemic heart disease patients. The changes in the endocannabinoid system in ischemics may contribute to cardiac dysfunction and therefore represents a potential therapeutic target.
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Affiliation(s)
- Giuseppe Cappellano
- Department of Health Sciences, Università del Piemonte Orientale, Novara, Italy.
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Malinowska B, Baranowska-Kuczko M, Schlicker E. Triphasic blood pressure responses to cannabinoids: do we understand the mechanism? Br J Pharmacol 2012; 165:2073-88. [PMID: 22022923 DOI: 10.1111/j.1476-5381.2011.01747.x] [Citation(s) in RCA: 66] [Impact Index Per Article: 5.1] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/12/2022] Open
Abstract
The cannabinoids comprise three major classes of substances, including compounds derived from the cannabis plant (e.g. Δ(9) -tetrahydrocannabinol and the chemically related substances CP55940 and HU210), endogenously formed (e.g. anandamide) and synthetic compounds (e.g. WIN55212-2). Beyond their psychotropic effects, cannabinoids have complex effects on blood pressure, including biphasic changes of Δ(9) -tetrahydrocannabinol and WIN55212-2 and an even triphasic effect of anandamide. The differing pattern of blood pressure changes displayed by the three types of compounds is not really surprising since, although they share an agonistic effect at cannabinoid CB(1) and CB(2) receptors, some compounds have additional effects. In particular, anandamide is known for its pleiotropic effects, and there is overwhelming evidence that anandamide influences blood pressure via (i) CB(1) receptors, (ii) TRPV1 receptors, (iii) endothelial cannabinoid receptors and (iv) degradation products. This review is dedicated to the description of the effects of externally added cannabinoids on cardiovascular parameters in vivo. First, the cardiovascular effects of cannabinoids in anaesthetized animals will be highlighted since most data have been generated in experiments of that type. The text will follow the three phases of anandamide on blood pressure, and we will check to which extent cardiovascular changes elicited by other cannabinoids show overlap with those effects or differ. The second part will be dedicated to the cardiovascular effects of the cannabinoids in conscious animals. In the third part, cardiovascular effects in humans will be discussed, and similarities and differences with respect to the data from animals will be examined.
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Affiliation(s)
- Barbara Malinowska
- Zakład Fizjologii i Patofizjologii Doświadczalnej, Uniwersytet Medyczny w Białymstoku, ul. Mickiewicza 2A, Białystok, Poland
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Lacerda-Miranda G, Soares VM, Vieira AKG, Lessa JG, Rodrigues-Cunha ACS, Cortez E, Garcia-Souza EP, Moura AS. Ghrelin signaling in heart remodeling of adult obese mice. Peptides 2012; 35:65-73. [PMID: 22407166 DOI: 10.1016/j.peptides.2012.02.025] [Citation(s) in RCA: 13] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 11/01/2011] [Revised: 02/29/2012] [Accepted: 02/29/2012] [Indexed: 11/18/2022]
Abstract
Ghrelin, an endogenous ligand of the growth hormone secretagogue receptor (GHS-R), has been suggested to be associated to obesity, insulin secretion, cardiovascular growth and homeostasis. GHS-R has been found in most of the tissues, and among the hormone action it is included the regulation of heart energy metabolism. Therefore, hypernutrition during early life leads to obesity, induces cardiac hypertrophy, compromises myocardial function, inducing heart failure in adulthood. We examined ghrelin signaling process in cardiac remodeling in these obese adult mice. The cardiomyocytes (cmy) of left ventricle were analyzed by light microscopy and stereology, content and phosphorilation of cardiac proteins: ghrelin receptor (growth hormone secretagogue receptor 1a, GHSR-1a), protein kinase B (AKT and pAKT), phosphatidil inositol 3 kinase (PI3K), AMP-activated protein kinase (AMPK and pAMPK) and actin were achieved by Western blotting. GHSR-1a gene expression was analyzed by Real Time-PCR. We observed hyperglycemia and higher liver and visceral fat weight in obese when compared to control group. Obese mice presented a marked increase in heart weight/tibia length, indicating an enlarged heart size or a remodeling process. Obese mice had increased GHSR-1a content and expression in the heart associated to PI3K content and increased AKT content and phosphorylation. In contrast, AMPK content and phosphorylation in heart was not different between experimental groups. Ghrelin plasma levels in obese group were decreased when compared to control group. Our data suggest that remodeled myocardial in adult obese mice overnourished in early life are associated with higher phosphorylation of GHSR-1a, PI3K and AKT but not with AMPK.
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Affiliation(s)
- Glauciane Lacerda-Miranda
- Department of Physiology, Institute of Biology, State University of Rio de Janeiro, Avenue 28 de setembro, 87 Fundos, 5 andar, Vila Isabel, Rio de Janeiro 20551-030, Brazil
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Hillard CJ, Weinlander KM, Stuhr KL. Contributions of endocannabinoid signaling to psychiatric disorders in humans: genetic and biochemical evidence. Neuroscience 2011; 204:207-29. [PMID: 22123166 DOI: 10.1016/j.neuroscience.2011.11.020] [Citation(s) in RCA: 115] [Impact Index Per Article: 8.2] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/03/2011] [Revised: 11/05/2011] [Accepted: 11/08/2011] [Indexed: 11/28/2022]
Abstract
The endocannabinoid signaling system is a widespread, neuromodulatory system in brain and is also widely utilized in the periphery to modulate metabolic functions and the immune system. Preclinical data demonstrate that endocannabinoid signaling is an important stress buffer and modulates emotional and cognitive functions. These data suggest the hypothesis that endocannabinoid signaling could be dysfunctional in a number of mental disorders. Genetic polymorphisms in the human genes for two important proteins of the endocannabinoid signaling system, the CB1 cannabinoid receptor (CB1R) and fatty acid amide hydrolase (FAAH), have been explored in the context of normal and pathological conditions. In the case of the gene for FAAH, the mechanistic relationships among the common genetic polymorphism, the expression of the FAAH protein, and its likely impact on endocannabinoid signaling are understood. However, multiple polymorphisms in the gene for the CB1R occur and are associated with human phenotypic differences without an understanding of the functional relationships among the gene, mRNA, protein, and protein function. The endocannabinoid ligands are found in the circulation, and several studies have identified changes in their concentrations under various conditions. These data are reviewed for the purpose of generating hypotheses and to encourage further studies in this very interesting and important area.
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Affiliation(s)
- C J Hillard
- Department of Pharmacology and Neuroscience Research Center, Medical College of Wisconsin, Milwaukee, WI, USA.
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Zoerner AA, Gutzki FM, Batkai S, May M, Rakers C, Engeli S, Jordan J, Tsikas D. Quantification of endocannabinoids in biological systems by chromatography and mass spectrometry: A comprehensive review from an analytical and biological perspective. Biochim Biophys Acta Mol Cell Biol Lipids 2011; 1811:706-23. [DOI: 10.1016/j.bbalip.2011.08.004] [Citation(s) in RCA: 120] [Impact Index Per Article: 8.6] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/04/2011] [Revised: 08/11/2011] [Accepted: 08/12/2011] [Indexed: 11/26/2022]
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Liao Y, Bin J, Asakura M, Xuan W, Chen B, Huang Q, Xu D, Ledent C, Takashima S, Kitakaze M. Deficiency of type 1 cannabinoid receptors worsens acute heart failure induced by pressure overload in mice. Eur Heart J 2011; 33:3124-33. [DOI: 10.1093/eurheartj/ehr246] [Citation(s) in RCA: 19] [Impact Index Per Article: 1.4] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 11/13/2022] Open
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