PARP Inhibition Restores Erectile Function by Suppressing Corporal Smooth Muscle Apoptosis in Diabetic Rats
PARP Inhibition Restores Erectile Function by Suppressing Corporal Smooth Muscle Apoptosis in Diabetic Rats
复制标题
PARP 抑制通过抑制糖尿病大鼠下体平滑肌细胞凋亡恢复勃起功能
DOI：
10.1111/j.1743-6109.2010.02176.x
复制
发表时间：
2011-04-01
影响因子：
3.5
通讯作者：
Wang, Zhong
中科院分区：
文献类型：
--
作者：
Li, Wen Ji;Zhou, Juan;Wang, Zhong
介绍。糖尿病相关性勃起功能障碍（ED）的一个重要机制被认为与细胞凋亡增加、胶原沉积增加和海肌体平滑肌含量减少有关。目的：探讨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了细胞凋亡的诱导，以及PARP特异性抑制剂3-氨基苯甲酰胺（3-AB）的使用是否能促进机体凋亡的发生。方法：将8周龄雄性Sprague-Dawley大鼠随机分为3组：同龄对照组(C)、糖尿病对照组（DM）和3-AB治疗糖尿病组（DM + 3-AB）。腹腔注射链脲佐菌素（50 mg/kg）诱导糖尿病。诱导糖尿病8周后，DM + 3-AB组给予3-AB （30 mg/kg/d, ig）治疗4周。主要结果测量。糖尿病诱导后12周，通过海绵体神经刺激评估勃起功能。对阴茎组织进行细胞凋亡、马松三色染色和平滑肌α -肌动蛋白免疫组织化学分析。Western blot检测多聚腺苷核糖（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蛋白（Bax）和凋亡诱导因子（AIF）的表达。结果dm组勃起功能受损，PARP活性升高，下体细胞凋亡增加，平滑肌含量降低。DM组细胞中磷酸化akt、磷酸化bad、Bcl-2的表达降低，ATP和NAD+浓度降低，MDA浓度升高，Bax表达升高，AIF核易位升高，caspase-3活性升高。3-AB治疗恢复了勃起功能，并显著逆转了除mda增加外的所有分子和组织学改变。糖尿病大鼠阴茎PARP通路的过度激活通过能量消耗、Akt磷酸化抑制和线粒体凋亡通路的激活等途径促进下体细胞凋亡，导致ED；这些事件可以通过3-AB治疗来预防。李文军，周军，李斌，王华，彭彦斌，王铮。PARP抑制通过抑制糖尿病大鼠下体平滑肌细胞凋亡恢复勃起功能。性医学杂志2011；8:1072-1082。
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. Li WJ, Zhou J, Li B, Wang H, Peng YB, and Wang Z. PARP inhibition restores erectile function by suppressing corporal smooth muscle apoptosis in diabetic rats. J Sex Med 2011;8:1072-1082.