TY - JOUR
T1 - Fatty acid amide hydrolase is a key regulator of endocannabinoid-induced myocardial tissue injury
AU - Mukhopadhyay, Partha
AU - Horváth, Bela
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
N1 - Funding Information:
This study was supported by the Intramural Research Program of the National Institutes of Health/NIAAA (to P.P.). Dr. Horváth was supported by an NKTH-OTKA-EU 7FW fellowship (MB08-A 80238). The authors are indebted to Dr. Murali C. Krishna for generously providing his resources and expertise with EPR measurements and Dr. George Kunos for providing support and resources for the completion of this study. Dr. Pacher dedicates this study to his beloved mother Iren Bolfert, who died from the cardiovascular complications of chemotherapy.
PY - 2011/1/1
Y1 - 2011/1/1
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 CB1 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 CB1 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 CB1 receptors by endocannabinoids.
AB - 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 CB1 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 CB1 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 CB1 receptors by endocannabinoids.
KW - Cannabinoid receptors
KW - Cardiomyopathy
KW - Cell death
KW - Endocannabinoids
KW - Free radicals
KW - Nitrosative stress
KW - Oxidative stress
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U2 - 10.1016/j.freeradbiomed.2010.11.002
DO - 10.1016/j.freeradbiomed.2010.11.002
M3 - Article
C2 - 21070851
AN - SCOPUS:78650716667
SN - 0891-5849
VL - 50
SP - 179
EP - 195
JO - Free Radical Biology and Medicine
JF - Free Radical Biology and Medicine
IS - 1
ER -