Sildenafil restores endothelial function in the apolipoprotein E knockout mouse

Journal of Translational Medicine

Research

Isabele B S Gomes¹  Silvana S Meyrelles²  Camille M Balarini²  Agata L Gava³  Elisardo C Vasquez⁴  Marcos A Leal⁵  Thiago M C Pereira⁶ 

[1] Dept. of Pharmaceutical Sciences, Health Sciences Center, Federal University of Espirito Santo, Vitoria, ES, Brazil;Dept. of Physiological Sciences, Health Sciences Center, Federal University of Espirito Santo, Vitoria, ES, Brazil;Dept. of Physiological Sciences, Health Sciences Center, Federal University of Espirito Santo, Vitoria, ES, Brazil;Biotechnology Graduate Program, Health Sciences Center, Federal University of Espirito Santo, Vitoria, ES, Brazil;Dept. of Physiological Sciences, Health Sciences Center, Federal University of Espirito Santo, Vitoria, ES, Brazil;Emescam College of Health Sciences, Vitoria, ES, Brazil;Lab Transgenes and Cardiovascular Control, Dept. of Physiological Sciences, Health Sciences Center, Federal University of Espirito Santo, Av Marechal Campos 1468, 29042-755, Vitoria, ES, Brazil;Emescam College of Health Sciences, Vitoria, ES, Brazil;Federal Institute of Education, Science and Technology (IFES), Vila Velha, ES, Brazil;Department of Pharmaceutical Sciences, University of Vila Velha, Vila Velha, ES, Brazil;

关键词: Atherosclerosis;    ApoE knockout mice;    Sildenafil;    Nitric oxide;    Oxidative stress;    Endothelial dysfunction;    PDE5;    cGMP;   

DOI  :  10.1186/1479-5876-11-3

 received in 2012-10-04, accepted in 2013-01-02,  发布年份 2013

来源: Springer

【 摘 要 】

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.

【 授权许可】

Unknown   
© Balarini et al.; licensee BioMed Central Ltd. 2013. This article is published under license to BioMed Central Ltd. This is an Open Access article distributed under the terms of the Creative Commons Attribution License (http://creativecommons.org/licenses/by/2.0), which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited.