Sildenafil Promotes eNOS Activation and Inhibits NADPH Oxidase in the Transgenic Sickle Cell Mouse Penis |
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| Affiliation: | 2. Pulmonary, Allergy and Critical Care Medicine, University of Pittsburgh Medical Center, Pittsburgh, PA, USA;2. Academy of Public Health, Anhui Medical University, Hefei, Anhui, China;3. Academy of Public Health, Xiangya School of Medicine, Central South University, Changsha, Hunan, China;4. Department of Urology, Anqing Affiliated Hospital of Anhui Medical University, Anqing, Anhui, China;5. Department of Urology, Huaibei People''s Hospital, Huaibei, Anhui, China;2. Department of Urology, Korea University Medical Center Guro Hospital, Seoul, Republic of Korea;3. Department of Urology, Chonnam National University, Gwangju, Republic of Korea;4. Department of Urology, Chonbuk National University, Jeonju, Republic of Korea;5. Department of Urology, Pusan National University, Busan, Republic of Korea;11. Department of Urology, Sungkyunkwan University, Seoul, Republic of Korea;2. Department of Radiology, Site Director North Shore Long Island Jewish at Great Neck, Great Neck, NY, USA;1. Department of Biology, College of Natural Sciences, Kangwon National University, Chuncheon 200-701, Republic of Korea;2. Department of Biochemistry, College of Natural Sciences, Kangwon National University, Chuncheon 200-701, Republic of Korea;3. College of Pharmacy, Catholic University, Daegu 712-702, Republic of Korea |
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| Abstract: | IntroductionSickle cell disease (SCD)‐associated vasculopathy in the penis is characterized by aberrant nitric oxide and phosphodiesterase (PDE) 5 signaling, and by increased oxidative stress. Preliminary clinical trials show that continuous treatment with PDE5 inhibitor sildenafil unassociated with sexual activity decreases priapic activity in patients with SCD. However, the mechanism of its vasculoprotective effect in the penis remains unclear.AimsWe evaluated whether continuous administration of PDE5 inhibitor sildenafil promotes eNOS function at posttranslational levels and decreases superoxide‐producing enzyme NADPH oxidase activity in the sickle cell mouse penis.MethodsSCD transgenic mice were used as an animal model of SCD. WT mice served as controls. Mice received treatment with the PDE5 inhibitor sildenafil (100 mg/kg/day) or vehicle for 3 weeks. eNOS phosphorylation on Ser‐1177 (positive regulatory site), eNOS interactions with heat‐shock protein 90 (HSP90) (positive regulator), phosphorylated AKT (upstream mediator of eNOS phosphorylation on Ser‐1177), an NADPH oxidase catalytic subunit gp91(phox), and a marker of oxidative stress (4‐hydroxy‐2‐nonenal [HNE]) were measured by Western blot.Main Outcome MeasuresEffect of continuous sildenafil treatment on eNOS posttranslational activation, NADPH oxidase catalytic subunit, and oxidative stress in the penis of the sickle cell mouse.ResultsContinuous treatment with sildenafil reversed (P < 0.05) the abnormalities in protein expressions of P‐eNOS (Ser‐1177), eNOS/HSP90 interaction, P‐AKT, protein expression of gp91(phox), and 4‐HNE, in the sickle cell mouse penis. Sildenafil treatment of WT mice did not affect any of these parameters.ConclusionOur findings that sildenafil enhances eNOS activation and inhibits NADPH oxidase function in the sickle cell mouse penis offers a vasculoprotective molecular basis for the therapeutic effect of sildenafil in the penis in association with SCD. Musicki B, Bivalacqua TJ, Champion HC, and Burnett AL. Sildenafil promotes eNOS activation and inhibits NADPH oxidase in the transgenic sickle cell mouse penis. J Sex Med 2014;11:424–430. |
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