Genetic deletion of fatty acid amide hydrolase is associated with anti‐inflammatory cardiovascular phenotype in mice

Abstract

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 approach for the treatment of various inflammatory disorders. Here, we have investigated the age‐associated decline of cardiac function and changes in inflammatory gene expression, nitrative stress, and apoptosis in FAAH knockout (−/−) mice and their wild‐type (+/+) littermates. There was no difference in the cardiac function between the young (8 weeks old) FAAH(−/−) and wild type mice. In contrast, the decline in cardiac function, increased myocardial gene expression of TNF‐alpha, gp91phox, MMP‐2, MMP‐9, caspase‐3/9; the myocardial iNOS expression, nitrotyrosine formation, PARP cleavage; and the caspase‐3/9 activity observed in the aging (<28 mo‐old) FAAH(+/+) mice, were largely attenuated in the knockouts. There was no difference in the myocardial CB1 and CB2 receptor expression between young and aging FAAH(−/−) and FAAH(+/+) mice. 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.