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

Academic Article
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Overview

authors

  • Batkai, S.
  • Rajesh, M.
  • Mukhopadhyay, P.
  • Haska, G.
  • Liaudet, L.
  • Cravatt, Benjamin
  • Csiszar, A.
  • Ungvari, Z.
  • Pacher, P.

publication date

  • August 2007

journal

  • American Journal of Physiology-Heart and Circulatory Physiology  Journal

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 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.

subject areas

  • Aging
  • Amidohydrolases
  • Animals
  • Apoptosis
  • Arachidonic Acids
  • Cell Adhesion
  • Cells, Cultured
  • Coronary Vessels
  • Endocannabinoids
  • Endothelial Cells
  • Gene Expression Regulation
  • Humans
  • Inflammation
  • Intercellular Adhesion Molecule-1
  • Mice
  • Mice, Knockout
  • Monocytes
  • Myocardium
  • NF-kappa B
  • Polyunsaturated Alkamides
  • Reactive Nitrogen Species
  • Receptors, Cannabinoid
  • Tumor Necrosis Factor-alpha
  • Vascular Cell Adhesion Molecule-1
  • Ventricular Dysfunction, Left
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Research

keywords

  • anandamide
  • cardiac function
  • endocannabinoids
  • pressure-volume relationship
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Identity

PubMed Central ID

  • PMC2225473

International Standard Serial Number (ISSN)

  • 0363-6135

Digital Object Identifier (DOI)

  • 10.1152/ajpheart.00373.2007

PubMed ID

  • 17434980
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Additional Document Info

start page

  • H909

end page

  • H918

volume

  • 293

issue

  • 2

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