Abstract 36: Fatty Acid Amide Hydrolase Deficiency Is Associated with a Vulnerable Plaque Phenotype in Atherosclerotic Mice
Elevated endocannabinoid levels are linked with the development of atherosclerotic vascular disease and coronary circulatory dysfunction in obese individuals, a precursor of coronary artery disease. However, it remains unclear whether endocannabinoid levels represent a risk factor or diagnostic biomarker for acute atherosclerotic vascular events. So far, a causal role of increased endocannabinoid levels in atherosclerotic plaque vulnerability and occurrence of acute clinical events has not been investigated. Here, we studied the involvement of fatty acid amide hydrolase (FAAH) deficiency, the major enzyme responsible for endocannabinoid anandamide degradation, in atherosclerotic plaque vulnerability.
We interbred apolipoprotein E-deficient (ApoE-/-) mice with FAAH-/- mice to generate ApoE-/-FAAH-/- mice and measured serum levels of anandamide and related FAAH metabolites palmitoyl- and oleoylethanolamide. We assessed atherosclerosis in ApoE-/- and ApoE-/-FAAH-/- mice after 5, 10 and 15 weeks on high cholesterol diet (HCD; 1.25% cholesterol).
Levels of FAAH metabolites anandamide, palmitoyl- and oleoylethanolamide were 1.4 to 2-fold higher in FAAH-/-ApoE-/-mice. FAAH deficiency attenuated atherosclerotic plaque size increase (by ∼50% in thoraco-abdominal aortas after 15 weeks HCD; n=7-10; P=0.007), but plaques had significantly lower content of smooth muscle cells (36% less after 10 weeks HCD in aortic sinuses; n=10-15; P=0.01) and increased matrix metalloproteinase MMP-9 expression (by 73%; P=0.049). There was no difference in macrophage content, but a 65% increase in neutrophil infiltrates (P=0.0007) in aortic sinus plaques from ApoE-/-FAAH-/- mice compared to ApoE-/- controls. This was accompanied by 1.9-fold increased chemokine CXCL1 mRNA levels (P =0.004) in mouse aortas. CXCL1 expression was confirmed by immunostaining which revealed colocalization with lesional macrophages. MMP-9 mainly colocalized with neutrophils rather than macrophages (correlation coefficient r: 0.6529; P=0.006).
Increased levels of endocannabinoid anandamide and related FAAH metabolite levels are associated with the development of smaller atherosclerotic plaques with more vulnerable phenotype.
- © 2012 by American Heart Association, Inc.