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Abstract：
Type 2 diabetes mellitus (T2DM) is a common cause of erectile dysfunction (ED). It has been demonstrated that G protein-coupled receptor kinase 2 (GRK2) overexpression contributes to diabetic endothelial dysfunction and oxidative stress, which also underlies ED in T2DM. We hypothesized that GRK2 overexpressed and attenuated endothelial function of the cavernosal tissue in a rat model of T2DM. T2DM rats were established by feeding with a high-fat diet (HFD) for 2 weeks and then administering two intraperitoneal (IP) injections of a low dose of streptozotocin (STZ), followed by continuous feeding with a HFD for 6 weeks. GRK2 was inhibited by IP injection of paroxetine, a selective GRK2 inhibitor, after STZ injection. Insulin challenge tests, intracavernous pressure (ICP), GRK2 expression, the protein kinase B (Akt)/endothelial nitric oxide synthase (eNOS) pathway, nicotinamide adenine dinucleotide phosphate (NADPH) oxidase subunit gp91 phox , nitric oxide (NO), reactive oxygen species (ROS) production, and apoptosis in cavernosal tissue were examined. Less response to insulin injection was observed in T2DM rats 2 weeks after HFD. Markedly increased GRK2 expression, along with impaired Akt/eNOS pathway, reduced NO production, increased gp91 phox expression and ROS generation, increased apoptosis and impaired erectile function were found in T2DM rats. Inhibition of GRK2 with paroxetine ameliorated Akt/eNOS signaling, restored NO production, downregulated NADPH oxidase, subsequently inhibited ROS generation and apoptosis, and ultimately preserved erectile function. These results indicated that GRK2 upregulation may be an important mechanism underlying T2DM ED, and GRK2 inhibition may be a potential therapeutic strategy for T2DM ED.
摘要：
2型糖尿病（T2DM）是勃起功能障碍（ED）的常见原因。已经证明G蛋白偶联受体激酶2(GRK2)过表达有助于糖尿病内皮功能障碍和氧化应激,这也是T2DM中ED的基础。我们假设GRK2在T2DM大鼠模型中过表达并减弱海绵体组织的内皮功能。通过高脂饮食（HFD）喂养2周，然后腹膜内（IP）注射两次低剂量链脲佐菌素（STZ）来建立T2DM大鼠，然后用HFD连续喂养6周。IP注射帕罗西汀抑制GRK2，一种选择性GRK2抑制剂，STZ注射后。胰岛素挑战测试，海绵体内压(ICP),GRK2表达，蛋白激酶B（Akt）/内皮型一氧化氮合酶（eNOS）途径，烟酰胺腺嘌呤二核苷酸磷酸（NADPH）氧化酶亚基gp91phox，一氧化氮（NO），活性氧（ROS）的产生，并检查海绵体组织中的细胞凋亡。在HFD后2周,在T2DM大鼠中观察到对胰岛素注射的反应较小。GRK2表达显著增加，随着Akt/eNOS通路受损，减少NO产生，gp91phox表达和ROS产生增加，2型糖尿病大鼠细胞凋亡增加,勃起功能受损。帕罗西汀抑制GRK2改善Akt/eNOS信号传导，没有恢复生产，下调NADPH氧化酶，随后抑制ROS的产生和凋亡，并最终保留了勃起功能。这些结果表明，GRK2上调可能是T2DMED的重要机制，和GRK2抑制可能是T2DMED的潜在治疗策略。
