The Endocannabinoid System and Heart Disease: The Role of Cannabinoid Receptor Type 2.

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“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.”

https://www.ncbi.nlm.nih.gov/pubmed/29412125

“Researchers suggest that THC and other cannabinoids, which are active at CB2, the cannabinoid receptor expressed on immune cells, may be valuable in treating atherosclerosis.” https://www.medscape.com/viewarticle/787468

“Cardiovascular disease: New use for cannabinoids”  https://www.nature.com/articles/nrd1733

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Cholesterol-induced stimulation of platelet aggregation is prevented by a hempseed-enriched diet.

Canadian Journal of Physiology and Pharmacology

“Hypercholesterolemia indirectly increases the risk for myocardial infarction by enhancing the ability of platelets to aggregate.

Diets enriched with polyunsaturated fatty acids (PUFAs) have been shown to reduce the detrimental effects of cholesterol on platelet aggregation.

This study investigated whether dietary hempseed, a rich source of PUFAs, inhibits platelet aggregation under normal and hypercholesterolemic conditions.

The results of this study demonstrate that when hempseed is added to a cholesterol-enriched diet, cholesterol-induced platelet aggregation returns to control levels.”

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Prospects for the Use of Cannabinoid Receptor Ligands for the Treatment of Metabolic Syndrome and Atherosclerosis: Analysis of Experimental and Clinical Data.

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“An antagonist of central cannabinoid CB1 receptors rimonabant causes weight loss in patients with obesity and metabolic syndrome, improves blood lipid parameters, increases the adiponectin level, decreases the rate of glucose and glycosylated hemoglobin in patients with diabetes mellitus type-2. However, rimonabant adverse effects include depression, anxiety, nausea, and dizziness which are apparently due to the blockade of central CB1 receptors.

In mice with a high-calorie diet, we defined that the blockade of peripheral CB1 receptors prevents obesity, steatosis of the liver, improves lipid and carbohydrate metabolism. Experimental studies suggest that peripheral CB2 receptor agonists have antiatherogenic effect. To validate the expediency of clinical research of CB2 receptor agonists in patients with atherosclerosis the comparative analysis of antiatherogenic properties of cannabinoids should be performed. In addition, experiments are needed on the combination use of cannabinoids with well-known antiatherogenic agents, such as statins.”

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Translating Endocannabinoid Biology into Clinical Practice: Cannabidiol for Stroke Prevention.

Mary Ann Liebert, Inc. publishers

“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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Monoglyceride lipase deficiency affects hepatic cholesterol metabolism and lipid-dependent gut transit in ApoE-/- mice.

 Image result for Oncotarget“Monoglyceride lipase (MGL) hydrolyzes monoglycerides (MGs) to glycerol and fatty acids. Among various MG species MGL also degrades 2-arachidonoylglycerol (2-AG), the most abundant endocannabinoid and potent activator of cannabinoid receptors (CBR) 1 and 2. MGL-knockout (-/-) mice exhibit pronounced 2-AG accumulation, but lack central cannabimimetic effects due to CB1R desensitization. We have previously shown that MGL affects plaque stability in apolipoprotein E (ApoE)-/- mice, an established animal model for dyslipidemia and atherosclerosis. In the current study, we investigated functional consequences of MGL deficiency on lipid and energy metabolism in ApoE/MGL double knockout (DKO) mice. MGL deficiency affected hepatic cholesterol metabolism by causing increased cholesterol elimination via the biliary pathway. Moreover, DKO mice exhibit lipid-triggered delay in gastric emptying without major effects on overall triglyceride and cholesterol absorption. The observed phenotype of DKO mice is likely not a consequence of potentiated CB1R signaling but rather dependent on the activation of alternative signaling pathways. We conclude that MGL deficiency causes complex metabolic changes including cholesterol metabolism and regulation of gut transit independent of the endocannabinoid system.”

https://www.ncbi.nlm.nih.gov/pubmed/28380440

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The role of exercise training and the endocannabinoid system in atherosclerotic plaque burden and composition in Apo-E-deficient mice.

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“We investigated the effect of combining exercise training and treatment with an endocannabinoid receptor 1 inhibitor (Rimonabant) on atherosclerosis burden and composition.

Both exercise and rimonabant treatments induced plaque regression and promoted plaque stability. The combined treatment failed to show additive or synergistic benefits relative to either intervention alone.”

https://www.ncbi.nlm.nih.gov/pubmed/28254386

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Overlapping molecular pathways between cannabinoid receptors type 1 and 2 and estrogens/androgens on the periphery and their involvement in the pathogenesis of common diseases (Review).

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“The physiological and pathophysiological roles of sex hormones have been well documented and the modulation of their effects is applicable in many current treatments.

On the other hand, the physiological role of endocannabinoids is not yet clearly understood and the endocannabinoid system is considered a relatively new therapeutic target.

The physiological association between sex hormones and cannabinoids has been investigated in several studies; however, its involvement in the pathophysiology of common human diseases has been studied separately.

Herein, we present the first systematic review of molecular pathways that are influenced by both the cannabinoids and sex hormones, including adenylate cyclase and protein kinase A, epidermal growth factor receptor, cyclic adenosine monophosphate response element-binding protein, vascular endothelial growth factor, proto-oncogene serine/threonine-protein kinase, mitogen-activated protein kinase, phosphatidylinositol-4,5-bisphosphate 3-kinase, C-Jun N-terminal kinase and extracellular-signal-regulated kinases 1/2.

Most of these influence cell proliferative activity.

Better insight into this association may prove to be beneficial for the development of novel pharmacological treatment strategies for many common diseases, including breast cancer, endometrial cancer, prostate cancer, osteoporosis and atherosclerosis.

The associations between cannabinoids, estrogens and androgens under these conditions are also presented and the molecular interactions are highlighted.”

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N-Oleoylethanolamine Reduces Inflammatory Cytokines and Adhesion Molecules in TNF-α-induced Human Umbilical Vein Endothelial Cells by Activating CB2 and PPAR-α.

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“Inflammation plays a pivotal role in the pathogenesis of atherosclerosis.

Peroxisome proliferator-activated receptor-alpha (PPAR-α) and cannabinoid receptor 2 (CB2) crucially impact the modulation of inflammation.

N-Oleoylethanolamine (OEA), a natural agonist of PPAR-α, can also up-regulate the expression of CB2 in human umbilical vein endothelial cells (HUVECs) and further shows an antiatherosclerotic effect.

Our study was designed to determinate whether OEA could inhibit inflammation in HUVECs induced by tumor necrosis factor-α (TNF-α) and to identify the mechanism of OEA function.

These results suggest that OEA exerts anti-inflammatory and anti-adhesive effects on HUVECs.”

https://www.ncbi.nlm.nih.gov/pubmed/27281236

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Cannabidiol-2′,6′-dimethyl ether as an effective protector of 15-lipoxygenase-mediated low-density lipoprotein oxidation in vitro.

“15-Lipoxygenase (15-LOX) is one of the key enzymes responsible for the formation of oxidized low-density lipoprotein (ox-LDL), a major causal factor for atherosclerosis.

We have recently reported that cannabidiol-2′,6′-dimethyl ether (CBDD) is a selective and potent inhibitor of 15-LOX-catalyzed linoleic acid oxygenation.

The results obtained demonstrate that CBDD is a potent and selective inhibitor of ox-LDL formation generated by the 15-LOX pathway.

These studies establish CBDD as both an important experimental tool for characterizing 15-LOX-mediated ox-LDL formation, and as a potentially useful therapeutic agent for treatment of atherosclerosis.

In sum, these findings suggest that CBDD may be a useful adjuvant in the treatment of atherosclerosis as well as an experimental tool for analyzing the mechanistic details of PUFAs oxygenation by 15-LOX.”

https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4012644/

“Cannabidiol-2′,6′-dimethyl ether, a cannabidiol derivative, is a highly potent and selective 15-lipoxygenase inhibitor. Thus, 15-LOX is suggested to be involved in development of atherosclerosis, and CBDD may be a useful prototype for producing medicines for atherosclerosis.”  http://www.ncbi.nlm.nih.gov/pubmed/19406952

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Selective activation of CB2 receptor improves efferocytosis in cultured macrophages.

“Recent evidence indicates that the defective ability to clear apoptotic cells by macrophages (efferocytosis) and the resultant apoptotic cells accumulation in atherosclerotic plaques play an important role during the progression of unstable plaques.

The cannabinoid type 2 receptor (CB2), has recently been emerging as a new target to reduce vulnerability and promote stability of plaques, however, the underlying mechanisms have not been studied in detail. In the present study, we investigated whether selective activation of CB2 improves efferocytosis of macrophages.

SIGNIFICANCE:

The selective activation of CB2 improves efferosytosis of normal-cultured and OxLDL-loaded macrophages, which might provide a novel mechanism on how CB2 activation reduces vulnerability and promotes stability of atherosclerotic plaques.”

http://www.ncbi.nlm.nih.gov/pubmed/27474129

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