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: 5.27). 11/2010; 50(1):179-95. DOI: 10.1016/j.freeradbiomed.2010.11.002
Source: PubMed

ABSTRACT 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.

  • [Show abstract] [Hide abstract]
    ABSTRACT: Recognized as a "disease modifier", physical activity (PA) is increasingly viewed as a more holistic, cost-saving method for prevention, treatment and management of human disease conditions. The traditional view that PA engages the monoaminergic and endorphinergic systems has been challenged by the discovery of the endocannabinoid system (ECS), composed of endogenous lipids, their target receptors, and metabolic enzymes. Indeed, direct and indirect evidence suggests that the ECS might mediate some of the PA-triggered effects throughout the body. Moreover, it is now emerging that PA itself is able to modulate ECS in different ways. Against this background, in the present review we shall discuss evidence of the cross-talk between PA and the ECS, ranging from brain to peripheral districts and highlighting how ECS must be tightly regulated during PA, in order to maintain its beneficial effects on cognition, mood, and nociception, while avoiding impaired energy metabolism, oxidative stress, and inflammatory processes.
    Cellular and Molecular Life Sciences CMLS 02/2014; · 5.86 Impact Factor
  • Source
    [Show abstract] [Hide abstract]
    ABSTRACT: BACKGROUND AND PURPOSE Cannabinoid CB2 receptor activation has been reported to attenuate myocardial, cerebral and hepatic ischaemia‐reperfusion (I/R) injury.EXPERIMENTAL APPROACH We have investigated the effects of a novel CB2 receptor agonist ((1S,4R)‐2‐(2,6‐dimethoxy‐4‐(2‐methyloctan‐2‐yl)phenyl)‐7,7‐dimethylbicyclo[2.2.1]hept‐2‐en‐1‐yl)methanol (HU‐910) on liver injury induced by 1 h of ischaemia followed by 2, 6 or 24 h of reperfusion, using a well‐established mouse model of segmental hepatic I/R.KEY RESULTS Displacement of [3H]CP55940 by HU‐910 from specific binding sites in CHO cell membranes transfected with human CB2 or CB1 receptors (hCB1/2) yielded Ki values of 6 nM and 1.4 µM respectively. HU‐910 inhibited forskolin‐stimulated cyclic AMP production by hCB2 CHO cells (EC50= 162 nM) and yielded EC50 of 26.4 nM in [35S]GTPγS binding assays using hCB2 expressing CHO membranes. HU‐910 given before ischaemia significantly attenuated levels of I/R‐induced hepatic pro‐inflammatory chemokines (CCL3 and CXCL2), TNF‐α, inter‐cellular adhesion molecule‐1, neutrophil infiltration, oxidative stress and cell death. Some of the beneficial effect of HU‐910 also persisted when given at the beginning of the reperfusion or 1 h after the ischaemic episode. Furthermore, HU‐910 attenuated the bacterial endotoxin‐triggered TNF‐α production in isolated Kupffer cells and expression of adhesion molecules in primary human liver sinusoidal endothelial cells stimulated with TNF‐α. Pretreatment with a CB2 receptor antagonist attenuated the protective effects of HU‐910, while pretreatment with a CB1 antagonist tended to enhance them.CONCLUSION AND IMPLICATIONS HU‐910 is a potent CB2 receptor agonist which may exert protective effects in various diseases associated with inflammation and tissue injury.LINKED ARTICLES This article is part of a themed section on Cannabinoids in Biology and Medicine. To view the other articles in this section visit . To view Part I of Cannabinoids in Biology and Medicine visit
    British Journal of Pharmacology 01/2012; 165(8). · 4.99 Impact Factor
  • [Show abstract] [Hide abstract]
    ABSTRACT: Background The role of endocannabinoids such as anandamide during atherogenesis remains largely unknown. Fatty acid amide hydrolase (FAAH) represents the key enzyme in anandamide degradation, and its inhibition is associated with subsequent higher levels of anandamide. Here, we tested whether selective inhibition of FAAH influences the progression of atherosclerosis in mice. Methods and Results Selective inhibition of FAAH using URB597 resulted in significantly increased plasma levels of anandamide compared to control, as assessed by mass spectrometry experiments in mice. Apolipoprotein E-deficient (ApoE-/-) mice were fed a high-fat, cholesterol-rich diet to induce atherosclerotic conditions. Simultaneously, mice received either the pharmacological FAAH inhibitor URB597 1mg/kg body weight (n = 28) or vehicle (n = 25) via intraperitoneal injection three times a week. After eight weeks, mice were sacrificed, and experiments were performed. Vascular superoxide generation did not differ between both groups, as measured by L012 assay. To determine whether selective inhibition of FAAH affects atherosclerotic plaque inflammation, immunohistochemical stainings of the aortic root were performed. Atherosclerotic plaque formation, vascular macrophage accumulation, as well as vascular T cell infiltration did not differ between both groups. Interestingly, neutrophil cell accumulation was significantly increased in mice receiving URB597 compared to control. Vascular collagen structures in atherosclerotic plaques were significantly diminished in mice treated with URB597 compared to control, as assessed by picro-sirius-red staining. This was accompanied by an increased aortic expression of matrix metalloproteinase-9, as determined by quantitative RT-PCR and westernblot analysis. Conclusion Inhibition of fatty acid amide hydrolase does not influence plaque size but increases plaque vulnerability in mice.
    Journal of Molecular and Cellular Cardiology 01/2013; · 5.15 Impact Factor


Available from
May 27, 2014