Sildenafil restores endothelial function in the apolipoprotein E knockout mouse
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RESEARCH
Open Access
Sildenafil restores endothelial function in the apolipoprotein E knockout mouse Camille M Balarini1, Marcos A Leal2, Isabele B S Gomes3, Thiago M C Pereira4,5, Agata L Gava1,6, Silvana S Meyrelles1 and Elisardo C Vasquez1,2,7*
Abstract Background: 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). 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. Methods: ApoE−/− mice treated with sildenafil (ViagraW, 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. Results: Sildenafil 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. Conclusion: This 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. Keywords: Atherosclerosis, ApoE knockout mice, Sildenafil, Nitric oxide, Oxidative stress, Endothelial dysfunction, PDE5, cGMP
Introduction 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 development of atherosclerotic plaques is influenced by oxidative stress, an imbalance between the accumulation of reactive * Correspondence: [email protected] 1 Dept. of Physiological Sciences, Health Sciences Center, Federal University of Espirito Santo, Vitoria, ES, Brazil
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