Yamanaka Masaki, Shirai Masato, Shiina Hiroaki, Tanaka Yuichiro, Tsujimura Akira, Matsumiya Kiyomi, Okuyama Akihiko, Dahiya Rajvir
Department of Urology, Veterans Affairs Medical Center, University of California at San Francisco, 4150 Clement Street, San Francisco, CA 94121, USA.
J Urol. 2003 Jul;170(1):291-7. doi: 10.1097/01.ju.0000060564.31122.2a.
We hypothesized that apoptosis is a downstream event in erectile dysfunction, and pro-apoptotic (Bak and Bax) and anti-apoptotic (Bcl-2 and Bcl-x) factors are involved in the etiology of diabetes induced erectile dysfunction. To test this hypothesis the intracavernous pressure of diabetic and insulin treated rats was measured to assess erectile function. Molecular and immunohistochemical analyses for apoptosis were then performed in rat crura to assess their role in diabetes induced erectile dysfunction and insulin treatment.
A total of 70, 6-month-old male Sprague-Dawley rats were divided into 2 groups, including a diabetic (50) and a healthy control (20) group. The diabetic group received intraperitoneal injection of streptozotocin (STZ) (Sigma-Aldrich Co., St. Louis, Missouri) to induce diabetes. Subcutaneous injection of insulin was administered daily to 9 diabetic rats 4 and 8 weeks after STZ injections for 4 and 8 weeks, respectively. Functional studies were performed in 9 diabetic rats each 4, 8 and 12 weeks after STZ injections, in 6 age matched control rats and in insulin treated rats at the termination of therapy. After the completion of functional study the penile crura were collected from rats for molecular and immunohistochemical studies.
Mean intracavernous pressure of diabetic rats was significantly lower than in control rats and the decrease in intracavernous pressure was significantly recovered by insulin treatment. Gene expressions of pro-apoptotic and anti-apoptotic factors were present in control, diabetic and insulin treated rat crura. However, anti-apoptotic protein expression was lacking in diabetic rat crura and pro-apoptotic protein expression was lost in insulin treated rat crura. The apoptotic index of diabetic rat crura was significantly higher than that of control rat crura and this index was significantly decreased in insulin treated rat crura.
There was a significant correlation between the decrease and recovery in intracavernous pressure, and protein expression of apoptotic factors in diabetic and insulin treated rat crura. To our knowledge this is the first report demonstrating that the relief of diabetes associated erectile dysfunction by insulin treatment is due to alterations in the protein expression of apoptotic factors in rat crura.
我们推测细胞凋亡是勃起功能障碍的下游事件，促凋亡因子（Bak和Bax）和抗凋亡因子（Bcl-2和Bcl-x）参与糖尿病性勃起功能障碍的病因。为验证这一假设，我们测量了糖尿病大鼠和胰岛素治疗大鼠的海绵体内压以评估勃起功能。随后在大鼠海绵体脚进行细胞凋亡的分子和免疫组化分析，以评估其在糖尿病性勃起功能障碍及胰岛素治疗中的作用。
总共70只6月龄雄性Sprague-Dawley大鼠被分为2组，包括糖尿病组（50只）和健康对照组（20只）。糖尿病组腹腔注射链脲佐菌素（STZ）（Sigma-Aldrich公司，密苏里州圣路易斯）以诱导糖尿病。在STZ注射后4周和8周，分别对9只糖尿病大鼠每日皮下注射胰岛素，持续4周和8周。在STZ注射后4周、8周和12周，对9只糖尿病大鼠、6只年龄匹配的对照大鼠以及胰岛素治疗大鼠在治疗结束时进行功能研究。功能研究完成后，从大鼠收集阴茎海绵体脚用于分子和免疫组化研究。
糖尿病大鼠的平均海绵体内压显著低于对照大鼠，胰岛素治疗可显著恢复海绵体内压的降低。促凋亡和抗凋亡因子的基因表达在对照、糖尿病和胰岛素治疗的大鼠海绵体脚中均有存在。然而，糖尿病大鼠海绵体脚中缺乏抗凋亡蛋白表达，而胰岛素治疗的大鼠海绵体脚中促凋亡蛋白表达缺失。糖尿病大鼠海绵体脚的凋亡指数显著高于对照大鼠海绵体脚，且该指数在胰岛素治疗的大鼠海绵体脚中显著降低。
糖尿病和胰岛素治疗的大鼠海绵体脚中，海绵体内压的降低与恢复以及凋亡因子的蛋白表达之间存在显著相关性。据我们所知，这是首次报道表明胰岛素治疗缓解糖尿病相关性勃起功能障碍是由于大鼠海绵体脚中凋亡因子蛋白表达的改变。
