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Inhibition of endocannabinoid-degrading enzyme fatty acid amide hydrolase increases atherosclerotic plaque vulnerability in mice.
- Source :
-
Journal of molecular and cellular cardiology [J Mol Cell Cardiol] 2014 Jan; Vol. 66, pp. 126-32. Date of Electronic Publication: 2013 Nov 25. - Publication Year :
- 2014
-
Abstract
- The role of endocannabinoids such as anandamide during atherogenesis remains largely unknown. Fatty acid amide hydrolase (FAAH) represents the key enzyme in anandamide degradation, and its inhibition is associated with subsequent higher levels of anandamide. Here, we tested whether selective inhibition of FAAH influences the progression of atherosclerosis in mice. Selective inhibition of FAAH using URB597 resulted in significantly increased plasma levels of anandamide compared to control, as assessed by mass spectrometry experiments in mice. Apolipoprotein E-deficient (ApoE(-/-)) mice were fed a high-fat, cholesterol-rich diet to induce atherosclerotic conditions. Simultaneously, mice received either the pharmacological FAAH inhibitor URB597 1mg/kg body weight (n=28) or vehicle (n=25) via intraperitoneal injection three times a week. After eight weeks, mice were sacrificed, and experiments were performed. Vascular superoxide generation did not differ between both groups, as measured by L012 assay. To determine whether selective inhibition of FAAH affects atherosclerotic plaque inflammation, immunohistochemical staining of the aortic root was performed. Atherosclerotic plaque formation, vascular macrophage accumulation, as well as vascular T cell infiltration did not differ between both groups. Interestingly, neutrophil cell accumulation was significantly increased in mice receiving URB597 compared to control. Vascular collagen structures in atherosclerotic plaques were significantly diminished in mice treated with URB597 compared to control, as assessed by picro-sirius-red staining. This was accompanied by an increased aortic expression of matrix metalloproteinase-9, as determined by quantitative RT-PCR and western blot analysis. Inhibition of fatty acid amide hydrolase does not influence plaque size but increases plaque vulnerability in mice.<br /> (Copyright © 2013 Elsevier Ltd. All rights reserved.)
- Subjects :
- Amidohydrolases genetics
Amidohydrolases metabolism
Animals
Apolipoproteins E deficiency
Apolipoproteins E genetics
Arachidonic Acids blood
Cell Movement drug effects
Diet, High-Fat
Dietary Fats adverse effects
Endocannabinoids blood
Gene Expression
Macrophages drug effects
Macrophages pathology
Mice
Mice, Knockout
Neutrophils drug effects
Neutrophils pathology
Plaque, Atherosclerotic drug therapy
Plaque, Atherosclerotic etiology
Plaque, Atherosclerotic pathology
Polyunsaturated Alkamides blood
Superoxides metabolism
Amidohydrolases antagonists & inhibitors
Benzamides pharmacology
Carbamates pharmacology
Enzyme Inhibitors pharmacology
Plaque, Atherosclerotic enzymology
Subjects
Details
- Language :
- English
- ISSN :
- 1095-8584
- Volume :
- 66
- Database :
- MEDLINE
- Journal :
- Journal of molecular and cellular cardiology
- Publication Type :
- Academic Journal
- Accession number :
- 24286707
- Full Text :
- https://doi.org/10.1016/j.yjmcc.2013.11.013