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Fatty acid amide hydrolase is a key regulator of endocannabinoid-induced myocardial tissue injury.
Free Radic Biol Med. 2011 Jan 01; 50(1):179-95.FR

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.

Authors+Show Affiliations

Laboratory of Physiologic Studies, National Institute on Alcohol Abuse and Alcoholism, National Cancer Institute, National Institutes of Health, Bethesda, MD 20892, USA.No affiliation info availableNo affiliation info availableNo affiliation info availableNo affiliation info availableNo affiliation info availableNo affiliation info availableNo affiliation info availableNo affiliation info availableNo affiliation info availableNo affiliation info availableNo affiliation info available

Pub Type(s)

Journal Article
Research Support, Non-U.S. Gov't

Language

eng

PubMed ID

21070851

Citation

Mukhopadhyay, Partha, et al. "Fatty Acid Amide Hydrolase Is a Key Regulator of Endocannabinoid-induced Myocardial Tissue Injury." Free Radical Biology & Medicine, vol. 50, no. 1, 2011, pp. 179-95.
Mukhopadhyay P, Horváth B, Rajesh M, et al. Fatty acid amide hydrolase is a key regulator of endocannabinoid-induced myocardial tissue injury. Free Radic Biol Med. 2011;50(1):179-95.
Mukhopadhyay, P., Horváth, B., Rajesh, M., Matsumoto, S., Saito, K., Bátkai, S., Patel, V., Tanchian, G., Gao, R. Y., Cravatt, B. F., Haskó, G., & Pacher, P. (2011). Fatty acid amide hydrolase is a key regulator of endocannabinoid-induced myocardial tissue injury. Free Radical Biology & Medicine, 50(1), 179-95. https://doi.org/10.1016/j.freeradbiomed.2010.11.002
Mukhopadhyay P, et al. Fatty Acid Amide Hydrolase Is a Key Regulator of Endocannabinoid-induced Myocardial Tissue Injury. Free Radic Biol Med. 2011 Jan 1;50(1):179-95. PubMed PMID: 21070851.
* Article titles in AMA citation format should be in sentence-case
TY - JOUR T1 - Fatty acid amide hydrolase is a key regulator of endocannabinoid-induced myocardial tissue injury. AU - Mukhopadhyay,Partha, AU - Horváth,Bėla, AU - Rajesh,Mohanraj, AU - Matsumoto,Shingo, AU - Saito,Keita, AU - Bátkai,Sándor, AU - Patel,Vivek, AU - Tanchian,Galin, AU - Gao,Rachel Y, AU - Cravatt,Benjamin F, AU - Haskó,György, AU - Pacher,Pál, Y1 - 2010/11/09/ PY - 2010/05/28/received PY - 2010/10/28/revised PY - 2010/11/01/accepted PY - 2010/11/13/entrez PY - 2010/11/13/pubmed PY - 2011/5/10/medline SP - 179 EP - 95 JF - Free radical biology & medicine JO - Free Radic Biol Med VL - 50 IS - 1 N2 - 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. SN - 1873-4596 UR - https://www.unboundmedicine.com/medline/citation/21070851/Fatty_acid_amide_hydrolase_is_a_key_regulator_of_endocannabinoid_induced_myocardial_tissue_injury_ L2 - https://linkinghub.elsevier.com/retrieve/pii/S0891-5849(10)01356-0 DB - PRIME DP - Unbound Medicine ER -