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Fatty acid amide hydrolase is a key regulator of the endocannabinoid‐induced myocardial tissue injury
Author(s) -
Horvath Bela,
Mukhopadhyay Partha,
Rajesh Mohanraj,
Matsumoto Shingo,
Saito Keita,
Bátkai Sándor,
Gao Yue R,
Cravatt Benjamin F,
Haskó György,
Pacher Pál
Publication year - 2011
Publication title -
the faseb journal
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.709
H-Index - 277
eISSN - 1530-6860
pISSN - 0892-6638
DOI - 10.1096/fasebj.25.1_supplement.1000.20
Subject(s) - fatty acid amide hydrolase , anandamide , endocannabinoid system , cannabinoid receptor , oxidative stress , pharmacology , reactive oxygen species , chemistry , cannabinoid , knockout mouse , receptor , biochemistry , medicine , antagonist
Increased levels of endocannabinoids in various cardiovascular disorders (e.g. 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 (the fatty acid amide hydrolase; FAAH) in the 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 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 littermates. The effects of DOX in FAAH knockout mice were attenuated by CB 1 receptor antagonists. Furthermore, anandamide induced enhanced cell death in human cardiomyocytes pretreated by FAAH antagonist, and enhanced 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, which is, at least in part, mediated by the activation of CB 1 receptors by endocannabinoids. This study was supported by the Intramural Research Program of NIH/NIAAA (P.P.) and OTKA MB08‐A 80238 (B.H.)