P606CB1 cannabinoid receptor antagonism inhibits balloon-induced neointima formation in atherosclerotic mice

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Abstract

Balloon angioplasty is a mechanic procedure aimed to improve blood flow in a stenotic artery, due to atherosclerosis. The resulting arterial injury stimulates vascular smooth muscle cell proliferation and inflammation, resulting in excessive neointima formation. Increasing evidence suggests an increase of endocannabinoid levels and receptor activation in pathological processes including atherosclerosis. Recently, we found that CB2 receptor activation is protective in a mouse model of balloon-induced arterial injury. However, the role of CB1 receptors and potential changes in endocannabinoid levels in this pathogenic condition remain unclear. The aim of this study was to investigate the role of endocannabinoids in balloon-induced injury and evaluate the therapeutic benefit of CB1 receptor antagonism in this pathology. We performed left common carotid balloon injury in weight-matched (25-30g) male apolipoprotein E-deficient (ApoE-/-) mice fed on high cholesterol (1.25%) diet for 8 weeks before the intervention. Aspirine was given a week before intervention to avoid thrombosis. Systemic levels of FAAH metabolite anandamide were determined before and after intervention. The effect of enhanced endocannabinoid levels on balloon injury was studied in high cholesterol-fed ApoE-/- mice lacking fatty acid amide hydrolase (ApoE-/-FAAH-/-), the enzyme allowing endocannabinoid anandamide degradation. To assess the therapeutic benefit of CB1 antagonism, ApoE-/- littermates were randomly assigned to receive daily intraperitoneal injection of either the synthetic CB1 antagonist AM281 (10 mg/kg) or vehicle control, with the first injection given 30 min. before balloon injury. We found significantly elevated systemic anandamide levels in ApoE-/- mice 7 days post-ballooning. At baseline, FAAH-deficient ApoE-/- mice had approximately 2-fold increases in systemic anandamide levels without further increases in response to balloon dilatation. Neointima formation was significantly enhanced in ApoE-/-FAAH-/- mice as compared to ApoE-/- controls. Conversely, we found significantly reduced neointima formation in injured vessels of ApoE-/- mice treated with AM281. This was associated with reduced staining for the proliferation marker PCNA, alpha-smooth muscle actin and CD68-positive macrophages within dilated arteries of AM281-treated mice.

In conclusion, our data indicate a detrimental role for endocannabinoids and CB1 receptors in response to acute arterial injury. Selective inhibition of CB1 receptors might offer a new therapeutic strategy for reducing restenosis in response to balloon angioplasty.

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