Abstract
BackgroundAtherosclerosis is an inflammatory process of the arterial walls and is initiated by endothelial dysfunction accompanied by an imbalance in the production of reactive oxygen species (ROS) and nitric oxide (NO). Sildenafil, a selective phosphodiesterase-5 (PDE5) inhibitor used for erectile dysfunction, exerts its cardiovascular effects by enhancing the effects of NO. The aim of this study was to investigate the influence of sildenafil on endothelial function and atherosclerosis progression in apolipoprotein E knockout (apoE−/−) mice.MethodsApoE−/− mice treated with sildenafil (Viagra®, 40 mg/kg/day, for 3 weeks, by oral gavage) were compared to the untreated apoE−/− and the wild-type (WT) mice.Aortic rings were used to evaluate the relaxation responses to acetylcholine (ACh) in all of the groups. In a separate set of experiments, the roles of NO and ROS in the relaxation response to ACh were evaluated by incubating the aortic rings with L-NAME (NO synthase inhibitor) or apocynin (NADPH oxidase inhibitor). In addition, the atherosclerotic lesions were quantified and superoxide production was assessed.ResultsSildenafil restored the vasodilator response to acetylcholine (ACh) in the aortic rings of the apoE−/− mice. Treatment with L-NAME abolished the vasodilator responses to ACh in all three groups of mice and revealed an augmented participation of NO in the endothelium-dependent vasodilation in the sildenafil-treated animals. The normalized endothelial function in sildenafil-treated apoE−/− mice was unaffected by apocynin highlighting the low levels of ROS production in these animals. Moreover, morphological analysis showed that sildenafil treatment caused approximately a 40% decrease in plaque deposition in the aorta.ConclusionThis is the first study demonstrating the beneficial effects of chronic treatment with sildenafil on endothelial dysfunction and atherosclerosis in a model of spontaneous hypercholesterolemia. These data indicate that the main mechanism of the beneficial effect of sildenafil on the endothelial function appears to involve an enhancement of the NO pathway along with a reduction in oxidative stress.
Highlights
Atherosclerosis, which can be defined as a chronic and progressive disease characterized by an inflammatory response of the arterial wall, is still a leading cause of death, mainly in the Western world [1,2]
The apolipoprotein E knockout mouse developed two decades ago [12,13], exhibits spontaneous hypercholesterolemia, accompanied by endothelial dysfunction similar to that observed in humans [4,14,15]
The aim of the present study was to test the hypothesis that chronic sildenafil treatment could revert or reduce the endothelial dysfunction and the progression of atherosclerosis observed in large vessels of apoE−/− mice
Summary
Atherosclerosis, which can be defined as a chronic and progressive disease characterized by an inflammatory response of the arterial wall, is still a leading cause of death, mainly in the Western world [1,2]. Sildenafil, which has largely been used for erectile dysfunction and pulmonary hypertension [7], is being used to enhance in vivo NO signaling in other vascular diseases as well [6]. This drug increases the bioavailability of the intracellular second messenger of NO (cGMP) by inhibition of phosphodiesterase-5 (PDE5). Atherosclerosis is an inflammatory process of the arterial walls and is initiated by endothelial dysfunction accompanied by an imbalance in the production of reactive oxygen species (ROS) and nitric oxide (NO). The normalized endothelial function in sildenafil-treated apoE−/− mice was unaffected by apocynin highlighting the low levels of ROS production in these animals. Morphological analysis showed that sildenafil treatment caused approximately a 40% decrease in plaque deposition in the aorta
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