Abstract
In this study we analysed the possible modulation of endocannabinoids and related molecules during atherosclerosis development in mice. Wild-type and apolipoprotein E knockout (ApoE −/−) mice were fed either normal chow or high-cholesterol diet for 8–12 weeks, and tissue endocannabinoid levels were measured by liquid chromatography–mass spectrometry. We found increased levels of 2-AG in aortas and visceral adipose tissue (VAT) of ApoE −/− mice fed on high-cholesterol diet for 12 weeks as compared to ApoE −/− mice fed on normal chow or wild-type mice fed on cholesterol. No significant difference in 2-AG levels was observed after 8 weeks of diet, and no changes in anandamide levels were found in any group. The levels of the anandamide-related mediators with anti-inflammatory or anti-lipogenic properties, palmitoylethanolamide (PEA) and oleoylethanolamide (OEA), decreased or increased only in VAT or in both tissues, respectively. Endocannabinoid- and OEA/PEA-degrading enzymes were expressed by macrophages within atherosclerotic lesions. In vitro, 2-AG and OEA-induced monocyte migration at 0.3–1 μM, which corresponds to the levels observed in aortas. PEA 1 μM also induced monocyte migration but counteracted the effect of 2-AG, whereas OEA enhanced it. Enhanced 2-AG levels in advanced atherosclerotic lesions may trigger the inflammatory process by recruiting more inflammatory cells and inducing extracellular matrix degradation via CB 2 receptors, and this possibility was supported in vitro but not in vivo by experiments with the CB 2 antagonist, SR144528.
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