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首页> 外文期刊>The journal of sexual medicine >PARP inhibition restores erectile function by suppressing corporal smooth muscle apoptosis in diabetic rats.
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PARP inhibition restores erectile function by suppressing corporal smooth muscle apoptosis in diabetic rats.

机译：PARP抑制可通过抑制糖尿病大鼠体内的平滑肌细胞凋亡来恢复勃起功能。

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INTRODUCTION: An important mechanism suggested to be responsible for diabetes-associated erectile dysfunction (ED) involves increased apoptosis, increased collagen deposition, and reduced smooth muscle content in the corpus cavernosum. AIM: To determine whether the activation of the pro-apoptotic poly(adenosine diphosphate ribose) polymerase (PARP) pathway is involved in the induction of corporal apoptosis, and whether the administration of 3-aminobenzamide (3-AB), a specific PARP inhibitor, could ameliorate ED in diabetic rats. METHODS: Male Sprague-Dawley rats (8-weeks-old) were randomly divided into three groups: age-matched controls (C), diabetic controls (DM), and 3-AB-treated diabetic group (DM + 3-AB). Diabetes was induced by intraperitoneal (ip) injection of streptozotocin (50 mg/kg). Eight weeks after the induction of diabetes, DM + 3-AB group treated with 3-AB (30 mg/kg/day, ip) for 4 weeks. MAIN OUTCOME MEASURES: At 12 weeks after diabetes induction, erectile function was assessed by cavernous nerve stimulation. Penile tissue was assessed for apoptosis, Masson's trichrome stain and immunohistochemical analysis for smooth muscle alpha actin. Expression of poly(ADP-ribose), phospho-protein kinase B (Akt), phospho-Bcl-2-associated death promoter (Bad), B-cell leukemia/lymphoma 2 (Bcl-2), Bcl-2-associated X Protein (Bax), and apoptosis-inducing factor (AIF) were evaluated by Western blot. Caspase-3 activity and malondialdehyde (MDA), adenosine triphosphate (ATP), and nicotinamide adenine dinucleotide (NAD+) concentrations were also determined. RESULTS: DM group showed impaired erectile function, increased PARP activity and corporal apoptosis, and decreased smooth muscle contents. Expression of phospho-Akt, phospho-Bad, Bcl-2, and concentrations of ATP and NAD+ were decreased in the DM group, whereas concentrations of MDA, expression of Bax, nuclear translocation of AIF, and caspase-3 activity were increased. Treatment with 3-AB restored erectile function and significantly reversed all molecular and histological alterations except for the increased MDA. CONCLUSION: Over-activation of penile PARP pathway in diabetic rats enhances corporal apoptosis via energy depletion, suppression of Akt phosphorylation, and activation of the mitochondrial apoptotic pathway, which results in ED; these event could be prevented by treatment with 3-AB.
机译：简介：提示与糖尿病相关的勃起功能障碍（ED）的重要机制涉及凋亡增加，胶原蛋白沉积增加以及海绵体中平滑肌含量降低。目的：确定促凋亡的聚腺苷二磷酸核糖聚合酶（PARP）通路的激活是否参与体细胞凋亡的诱导，以及是否施用特定的PARP抑制剂3-氨基苯甲酰胺（3-AB）可以改善糖尿病大鼠的ED。方法：将雄性Sprague-Dawley大鼠（8周龄）随机分为三组：年龄匹配的对照组（C），糖尿病对照组（DM）和3-AB治疗的糖尿病组（DM + 3-AB） 。腹膜内（ip）注射链脲佐菌素（50 mg / kg）可诱发糖尿病。糖尿病诱发八周后，DM + 3-AB组用3-AB（30 mg / kg / day，ip）进行4周治疗。主要观察指标：诱导糖尿病后12周，通过海绵体神经刺激评估勃起功能。评估阴茎组织的凋亡，Masson三色染色和平滑肌α肌动蛋白的免疫组织化学分析。聚（ADP-核糖），磷酸化蛋白激酶B（Akt），磷酸化Bcl-2相关死亡启动子（Bad），B细胞白血病/淋巴瘤2（Bcl-2），Bcl-2相关X的表达蛋白（Bax）和凋亡诱导因子（AIF）进行了蛋白质印迹评估。还测定了Caspase-3活性和丙二醛（MDA），三磷酸腺苷（ATP）和烟酰胺腺嘌呤二核苷酸（NAD +）的浓度。结果：DM组显示勃起功能受损，PARP活性增加和体细胞凋亡，平滑肌含量降低。 DM组磷酸化Akt，磷酸化Bad，Bcl-2的表达以及ATP和NAD +的浓度降低，而MDA的浓度，Bax的表达，AIF的核易位和caspase-3活性增加。用3-AB治疗可恢复勃起功能，并显着逆转除MDA升高外的所有分子和组织学改变。结论：糖尿病大鼠阴茎PARP通路的过度激活通过能量消耗，抑制Akt磷酸化和激活线粒体凋亡途径来增强体细胞凋亡，从而导致ED。这些事件可以通过3-AB治疗来预防。

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