Fatty acid amide hydrolase is a key regulator of endocannabinoid-induced myocardial tissue injury

Laboratory of Physiologic Studies, National Institute on Alcohol Abuse and Alcoholism, National Cancer Institute, National Institutes of Health, Bethesda, MD 20892, USA.
Free Radical Biology and Medicine (Impact Factor: 5.74). 11/2010; 50(1):179-95. DOI: 10.1016/j.freeradbiomed.2010.11.002
Source: PubMed


Previous studies have suggested that increased levels of endocannabinoids in various cardiovascular disorders (e.g., various forms of shock, cardiomyopathies, atherosclerosis) through the activation of CB(1) cannabinoid receptors may promote cardiovascular dysfunction and tissue injury. We have investigated the role of the main endocannabinoid anandamide-metabolizing enzyme (fatty acid amide hydrolase; FAAH) in myocardial injury induced by an important chemotherapeutic drug, doxorubicin (DOX; known for its cardiotoxicity mediated by increased reactive oxygen and nitrogen species generation), using well-established acute and chronic cardiomyopathy models in mice. The DOX-induced myocardial oxidative/nitrative stress (increased 4-hydroxynonenal, protein carbonyl, and nitrotyrosine levels and decreased glutathione content) correlated with multiple cell death markers, which were enhanced in FAAH knockout mice exhibiting significantly increased DOX-induced mortality and cardiac dysfunction compared to their wild type. The effects of DOX in FAAH knockouts were attenuated by CB(1) receptor antagonists. Furthermore, anandamide induced enhanced cell death in human cardiomyocytes pretreated with FAAH inhibitor and enhanced sensitivity to ROS generation in inflammatory cells of FAAH knockouts. These results suggest that in pathological conditions associated with acute oxidative/nitrative stress FAAH plays a key role in controlling the tissue injury that is, at least in part, mediated by the activation of CB(1) receptors by endocannabinoids.

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    • "The use of FAAH inhibitors, which will increase the tissue levels of OEA, PEA, and LEA, will also increase the tissue levels of anandamide. FAAH inhibitors have shown many positive biological effects in animal models of human pathologies, but most of these effects may primarily be due to an increase in the endogenous levels of anandamide followed by activation of cannabinoid receptors [59] [60] [61] [62] [63]. However, transiently upregulation of NAPE-PLD and thereby of the endogenous level of OEA in the small intestine by the use of an adenoviral vector [64] suggests that endogenous OEA may have a role in the regulation of food intake [65]. "
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    ABSTRACT: N-Acylethanolamine (NAE) and 2-monoacylglycerol (2-MAG) containing arachidonic acid are being called endocannabinoids since they can activate cannabinoid receptors. The same molecules containing stearic acid, palmitic acid, oleic acid, or linoleic acid cannot activate cannabinoid receptors, and are thus called non-endocannabinoid NAEs and 2-MAGs. However, these molecules do also have biological activities, e.g., via activation of the transcription factor PPARα, which mediate anti-inflammatory, antinociceptive, and anorectic effects. Furthermore, activation of the G-protein coupled receptor GPR119 in the small intestine could mediate release of the incretin hormone GLP-1. The present chapter describes the formation and degradation of these lipid molecules, as well as their pharmacology and their related drug targets.
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    • "e l s e v i e r . c o m / l o c a t e / i j c a r d doxorubicin-induced myocardial dysfunction [12] [13] [14], this may not be the case for conventional CHF induced by myocardial ischemia or pressure overload. In fact, a recent large-scale clinical trial (RESCENDO) showed that rimonabant did not improve major cardiovascular eventfree survival in obese patients with a previous history or increased risk of vascular disease at a mean follow-up of 14 months [15]. "
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    ABSTRACT: Background: The endocannabinoid system is known to play a role in regulating myocardial contractility, but the influence of cannabinoid receptor 1 (CB1) deficiency on chronic heart failure (CHF) remains unclear. In this study we attempted to investigate the effect of CB1 deficiency on CHF induced by pressure overload and the possible mechanisms involved. Methods and results: A CHF model was created by transverse aortic constriction (TAC) in both CB1 knockout mice and wild-type mice. CB1 knockout mice showed a marked increase of mortality due to CHF from 4 to 8 weeks after TAC (p=0.021). Five weeks after TAC, in contrast to wild-type mice, CB1 knockout mice had a higher left ventricular (LV) end-diastolic pressure, lower rate of LV pressure change (± dp/dt max), lower LV contractility index, and a larger heart weight to body weight ratio and lung weight to body weight ratio compared with wild-type mice (all p<0.05-0.001). Phosphorylation of the epidermal growth factor receptor (EGFR) and mitogen-activated protein kinases (P38 and ERK) was higher in CB1 knockout mice than that in wild-type mice. In cultured neonatal rat cardiomyocytes, a CB1 agonist reduced cAMP production stimulated by isoproterenol or forskolin, and suppressed phosphorylation of the EGFR, P38, and ERK, while the inhibitory effect of a CB1 agonist on EGFR phosphorylation was abrogated by CB1 knockdown. Conclusion: These findings indicate that cannabinoid receptor 1 inactivation promotes cardiac remodeling by enhancing the activity of the epidermal growth factor receptor and mitogen-activated protein kinases.
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    • "In the cardiovascular system, CB1 activation by endocannabinoids or synthetic ligands leads to complex cardiovascular depressive effects, implicated in the cardiovascular collapse associated with various forms of shock (21) and heart failure (26–28). CB1R activation in coronary artery endothelial cells (29), cardiomyocytes (26,27), and inflammatory cells (28,30) mediates MAPK activation, reactive oxygen species (ROS) generation, and inflammatory response promoting atherosclerosis (31) and cardiac dysfunction (27,28). Furthermore, elevated endocannabinoid plasma levels have recently been associated with coronary circulatory dysfunction in human obesity (32), and CB1R blockade or its genetic deletion attenuated proteinuria and/or vascular inflammation and cell death in experimental models of type 1 diabetic nephropathy (33) and/or retinopathy (34). "
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    ABSTRACT: Endocannabinoids and cannabinoid 1 (CB(1)) receptors have been implicated in cardiac dysfunction, inflammation, and cell death associated with various forms of shock, heart failure, and atherosclerosis, in addition to their recognized role in the development of various cardiovascular risk factors in obesity/metabolic syndrome and diabetes. In this study, we explored the role of CB(1) receptors in myocardial dysfunction, inflammation, oxidative/nitrative stress, cell death, and interrelated signaling pathways, using a mouse model of type 1 diabetic cardiomyopathy. Diabetic cardiomyopathy was characterized by increased myocardial endocannabinoid anandamide levels, oxidative/nitrative stress, activation of p38/Jun NH(2)-terminal kinase (JNK) mitogen-activated protein kinases (MAPKs), enhanced inflammation (tumor necrosis factor-α, interleukin-1β, cyclooxygenase 2, intracellular adhesion molecule 1, and vascular cell adhesion molecule 1), increased expression of CB(1), advanced glycation end product (AGE) and angiotensin II type 1 receptors (receptor for advanced glycation end product [RAGE], angiotensin II receptor type 1 [AT(1)R]), p47(phox) NADPH oxidase subunit, β-myosin heavy chain isozyme switch, accumulation of AGE, fibrosis, and decreased expression of sarcoplasmic/endoplasmic reticulum Ca(2+)-ATPase (SERCA2a). Pharmacological inhibition or genetic deletion of CB(1) receptors attenuated the diabetes-induced cardiac dysfunction and the above-mentioned pathological alterations. Activation of CB(1) receptors by endocannabinoids may play an important role in the pathogenesis of diabetic cardiomyopathy by facilitating MAPK activation, AT(1)R expression/signaling, AGE accumulation, oxidative/nitrative stress, inflammation, and fibrosis. Conversely, CB(1) receptor inhibition may be beneficial in the treatment of diabetic cardiovascular complications.
    Full-text · Article · Mar 2012 · Diabetes
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