摘要：

Objectives: It has been suggested that low-dose oral cannabinoid therapy with tetrahydrocannabinol (THC) reduces progression of atherosclerosis in mice. As THC also activates central CB1 receptors with subsequent psychoactive effects, it is not a therapeutic option in humans but isolated CB2 stimulation might be a promising approach for treating atherosclerosis. JWH 133 is a selective agonist for the CB2 receptor and possesses anti-inflammatory properties. We investigated whether this substance might influence the course of atherosclerosis in mice. Methods: Atherosclerosis prone apolipoprotein E-deficient (apoE-/-) mice were fed a high-cholesterol diet for six weeks to generate atherosclerotic conditions and concomitantly treated with placebo (n=5) or 10 mg/kgBW JWH 133 i.p. daily (n=5). Immunhistochemical stainings were performed to analyze plaque size and leukocyte infiltration. Vascular oxidative stress was measured by L012 chemiluminescence assays. FACS analysis was performed to quantify circulating endothelialprogenitor- cells (EPC). Aortic endothelial function was obtained in isolated aortic rings in organ chamber experiments. Results: As the central finding, treatment with JWH 133 attenuated atherosclerosis in mice. JWH 133-treated mice showed significantly diminished plaque size. Measurement of endothelial function revealed significantly improved endothelial dependent relaxation in apoE -/-mice treated with JWH 133 compared to placebo. Oxidative stress tended to be impaired in mice treated with JWH 133. Leukocyteinfiltration into the vessel wall and circulating EPC-levels did not differ between both groups. Conclusions: Selective CB2 receptor stimulation impacts vascular oxidative stress, improves endothelial function and ultimately attenuates atherosclerosis in mice. These data provide novel insights in the mode of action of the endocannabinoid system. Furthermore, CB2 stimulation may resemble a novel atheroprotective treatment option warranting further additional mechanistical and translational investigations.

展开