Bátkai S, Rajesh M, Mukhopadhyay P, Haskó G, Liaudet L, Cravatt BF, Csiszár A, Ungvári Z, Pacher P. Decreased age-related cardiac dysfunction, myocardial nitrative stress, inflammatory gene expression, and apoptosis in mice lacking fatty acid amide hydrolase. Am J Physiol Heart Circ Physiol 293: H909-H918, 2007. First published April 13, 2007; doi:10.1152/ajpheart.00373.2007.-Recent studies have uncovered important cross talk between inflammation, generation of reactive oxygen and nitrogen species, and lipid metabolism in the pathogenesis of cardiovascular aging. Inhibition of the endocannabinoid anandamide metabolizing enzyme, the fatty acid amide hydrolase (FAAH), is emerging as a promising novel approach for the treatment of various inflammatory disorders. In this study, we have investigated the age-associated decline of cardiac function and changes in inflammatory gene expression, nitrative stress, and apoptosis in FAAH knockout (FAAH Ϫ/Ϫ ) mice and their wild-type (FAAH ϩ/ϩ ) littermates. Additionally, we have explored the effects of anandamide on TNF-␣-induced ICAM-1 and VCAM-1 expression and monocyte-endothelial adhesion in human coronary artery endothelial cells (HCAECs). There was no difference in the cardiac function (measured by the pressure-volume conductance catheter system) between 2-to 3-mo-old (young) FAAH Ϫ/Ϫ and FAAH ϩ/ϩ mice. In contrast, the aging-associated decline in cardiac function and increased myocardial gene expression of TNF-␣, gp91phox, matrix metalloproteinase (MMP)-2, MMP-9, caspase-3 and caspase-9, myocardial inducible nitric oxide synthase protein expression, nitrotyrosine formation, poly (ADP-ribose)polymerase cleavage and caspase-3/9 activity, observed in 28-to 31-mo-old (aging) FAAH ϩ/ϩ mice, were largely attenuated in knockouts. There was no difference in the myocardial cannabinoid CB 1 and CB2 receptor gene expression between young and aging FAAH Ϫ/Ϫ and FAAH ϩ/ϩ mice. Anandamide dose dependently attenuated the TNF-␣-induced ICAM-1 and VCAM-1 expression, NF-B activation in HCAECs, and the adhesion of monocytes to HCAECs in a CB1-and CB2-dependent manner. These findings suggest that pharmacological inhibition of FAAH may represent a novel protective strategy against chronic inflammation, oxidative/nitrative stress, and apoptosis associated with cardiovascular aging and atherosclerosis. cardiac function; anandamide; pressure-volume relationship; endocannabinoids MODULATION OF THE ENDOCANNABINOID system is emerging as a novel approach for the therapy of various inflammatory, metabolic, cardiovascular, gastrointestinal, liver, and neurodegenerative disorders (reviewed in Refs. 32,35,47). The natural ligands [endocannabinoids: arachidonoyl ethanolamide or anandamide (AEA) and 2-arachidonoylglycerol (2-AG)], similarly to their synthetic analogs, exert various anti-inflammatory and other effects mediated through the activation of two known cannabinoid (CB) receptors: the CB 1 receptor, which is highly expressed in the brain (40) but is also present in peripheral tissues including ...