Toblli J E, Cao G, Angerosa M, Rivero M
Laboratory of Experimental Medicine, Hospital Alemán, School of Medicine, University of Buenos Aires, Buenos Aires, Argentina.
Int J Impot Res. 2015 Sep-Oct;27(5):182-90. doi: 10.1038/ijir.2015.13. Epub 2015 Jul 23.
Oxidative stress and nitrosative stress present in type 2 diabetes mellitus (T2DM) and metabolic syndrome (MS) induce inflammatory response in diverse tissues including cavernous tissue (CT). Heat-shock proteins (HSPs) have an important role in modulating and repairing tissue injury, although their participation in CT in T2DM is unclear. Beyond the specific action of phosphodiesterase type 5 inhibitors (PDE5i) on erectile function, it has been proposed that chronic administration of these agents improves endothelial function and ameliorates fibrotic changes. The aim of this study was to determine in CT of Zucker Diabetic Fatty (ZDF) rat, an experimental model of T2DM and MS: (1) the degree of oxidative stress and nitrosative stress; (2) the magnitude of inflammatory markers such as tumor necrosis factor-α (TNFα) and interleukin 6 (IL6); (3) immunoexpression of HSP70 and HSP27; (4) how a long-term PDE5i administration may modify these variables. For 6 months, (1) untreated ZDF; (2) ZDF+Sildenafil (Sil) and (3) control Lean Zucker Rat (LZR) received no treatment, were studied. Penises were processed for functional 'in vitro' studies, oxidative and nitrosative stress evaluation and immunohistochemistry in CT using TNFα; IL6; nitrotyrosine, HSP70 and HSP27 antibodies. ZDF+Sil presented better relaxation in corporal strips versus untreated ZDF. Furthermore, ZDF+Sil presented less lipoperoxidation in CT versus untreated ZDF. The activity of antioxidant enzymes CuZn superoxide dismutase (CuZnSOD) and glutathione peroxidase (GPx) was also reduced in untreated ZDF in CT along with a decrease in glutathione versus untreated ZDF. Nitrotyrosine expression was increased in untreated-ZDF rats versus ZDF+Sil and LZR. TNFα and IL6 were decreased in CT in ZDF+Sil versus untreated ZDF. Additionally, the expression of HSP70 and HSP27 was reduced in CT in ZDF+Sil versus untreated ZDF. In conclusion, this study provides substantial evidence supporting a protective role of a long-term therapy with Sil on CT in a recognized animal model of T2DM and MS.
2型糖尿病（T2DM）和代谢综合征（MS）中存在的氧化应激和亚硝化应激会在包括海绵体组织（CT）在内的多种组织中引发炎症反应。热休克蛋白（HSPs）在调节和修复组织损伤中起重要作用，尽管它们在T2DM的CT中的参与情况尚不清楚。除了5型磷酸二酯酶抑制剂（PDE5i）对勃起功能的特定作用外，有人提出长期使用这些药物可改善内皮功能并减轻纤维化改变。本研究的目的是在T2DM和MS的实验模型——Zucker糖尿病脂肪大鼠（ZDF）的CT中确定：（1）氧化应激和亚硝化应激的程度；（2）肿瘤坏死因子-α（TNFα）和白细胞介素6（IL6）等炎症标志物的水平；（3）HSP70和HSP27的免疫表达；（4）长期给予PDE5i如何改变这些变量。对6个月来未接受治疗的ZDF大鼠（1组）、ZDF+西地那非（Sil）大鼠（2组）和未接受治疗的对照瘦型Zucker大鼠（LZR，3组）进行了研究。对阴茎进行处理，用于“体外”功能研究、氧化和亚硝化应激评估以及使用TNFα、IL6、硝基酪氨酸、HSP70和HSP27抗体对CT进行免疫组织化学分析。与未治疗的ZDF相比，ZDF+Sil组的海绵体条带舒张情况更好。此外，与未治疗的ZDF相比，ZDF+Sil组CT中的脂质过氧化程度更低。与未治疗的ZDF相比，未治疗的ZDF大鼠CT中的抗氧化酶铜锌超氧化物歧化酶（CuZnSOD）和谷胱甘肽过氧化物酶（GPx）活性也降低，同时谷胱甘肽含量减少。与ZDF+Sil和LZR相比，未治疗的ZDF大鼠中硝基酪氨酸表达增加。与未治疗的ZDF相比，ZDF+Sil组CT中的TNFα和IL6减少。此外，与未治疗的ZDF相比，ZDF+Sil组CT中HSP70和HSP27的表达降低。总之，本研究提供了大量证据，支持在公认的T2DM和MS动物模型中，长期使用西地那非对CT具有保护作用。
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