serval:BIB_292AB7F34100
Decreased age-related cardiac dysfunction, myocardial nitrative stress, inflammatory gene expression, and apoptosis in mice lacking fatty acid amide hydrolase.
10.1152/ajpheart.00373.2007
17434980
000248488000004
Bátkai
S.
author
Rajesh
M.
author
Mukhopadhyay
P.
author
Haskó
G.
author
Liaudet
L.
author
Cravatt
B.F.
author
Csiszár
A.
author
Ungvári
Z.
author
Pacher
P.
author
article
2007-08
American Journal of Physiology. Heart and Circulatory Physiology
0363-6135
journal
293
2
H909-918
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-alpha-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-alpha, 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 CB(1) and CB(2) receptor gene expression between young and aging FAAH(-/-) and FAAH(+/+) mice. Anandamide dose dependently attenuated the TNF-alpha-induced ICAM-1 and VCAM-1 expression, NF-kappaB activation in HCAECs, and the adhesion of monocytes to HCAECs in a CB(1)- and CB(2)-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.
Aging/genetics
Aging/metabolism
Amidohydrolases/deficiency
Amidohydrolases/genetics
Animals
Apoptosis
Arachidonic Acids/metabolism
Cell Adhesion
Cells, Cultured
Coronary Vessels/cytology
Coronary Vessels/metabolism
Endothelial Cells/metabolism
Gene Expression Regulation
Humans
Inflammation/enzymology
Inflammation/genetics
Intercellular Adhesion Molecule-1/metabolism
Mice
Mice, Knockout
Monocytes/metabolism
Myocardium/enzymology
Myocardium/metabolism
NF-kappa B/metabolism
Polyunsaturated Alkamides/metabolism
Reactive Nitrogen Species/metabolism
Receptors, Cannabinoid/metabolism
Tumor Necrosis Factor-alpha/metabolism
Vascular Cell Adhesion Molecule-1/metabolism
Ventricular Dysfunction, Left/enzymology
Ventricular Dysfunction, Left/genetics
eng
60_published
peer-reviewed
Publication types: Comparative Study ; Journal Article
University of Lausanne
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