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Cardiovascular Aging

Decreased age-related cardiac dysfunction, myocardial nitrative stress, inflammatory gene expression, and apoptosis in mice lacking fatty acid amide hydrolase

¹Sections on Oxidative Stress Tissue Injury, Laboratory of Physiological Studies, National Institute on Alcohol Abuse and Alcoholism, National Institutes of Health, Bethesda, Maryland; ²Department of Surgery, University of Medicine and Dentistry, New Jersey-New Jersey Medical School, Newark, New Jersey; ³Department of Intensive Care Medicine, University Hospital, Lausanne, Switzerland; ⁴The Skaggs Institute for Chemical Biology and Department of Cell Biology, The Scripps Research Institute, La Jolla, California; and ⁵Department of Physiology, New York Medical College, Valhalla, New York

Submitted 24 March 2007 ; accepted in final form 13 April 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^–/–) mice and their wild-type (FAAH^+/+) 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^–/– and FAAH^+/+ 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^+/+ mice, were largely attenuated in knockouts. There was no difference in the myocardial cannabinoid CB₁ and CB₂ receptor gene expression between young and aging FAAH^–/– and FAAH^+/+ 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

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