ACE2/Ang-(1-7)/Mas轴在糖尿病性勃起功能障碍中的作用机制研究

Erectile dysfunction (ED) is a widespread disorder that affects millions of human beings worldwide. Diabetes mellitus is one of the most common causes of ED. Due to its complex pathogenesis, diabetic ED is more severe and more resistant to treatment compared with nondiabetic ED. The renin-angiotensin system (RAS) is a key modulator of cardiovascular homeostasis and evidence indicate that RAS also plays an essential role in the pathogenesis of diabetic ED. Ang-(1-7) is a bioactive member of the RAS, formed by angiotensin-converting enzyme 2 (ACE2), which activates the Mas receptor and promotes many beneficial cardiovascular outcomes, such as vasodilation, NO release and antiproliferative and antifibrotic effects. Within the erectile tissues, in an opposite way to Ang II, Ang-(1-7) has been shown to favor the erection. Our previous study has shown that ACE2 expression was significantly decreased in diabetic ED rat model, and activation of ACE2 by diminazene aceturate(DIZE) could obviously ameliorate penile fibrosis, which indicates an essential role of ACE2/Ang-(1-7)/Mas axis in diabetic erectile dysfunction. However, the underlying mechanism of Ang-(1-7)-mediated protection in diabetic erectile function is still poorly understood. Based on these findings, we plan to use diabetic rats as in vivo ED animal model and primary corpus cavernosum smooth muscle cells and endothelial cells in vitro coupled with pharmacological approaches to assess the exact role of ACE2/Ang-(1-7)/Mas axis in diabetic ED, and to determine the downstream intracellular signaling pathways of these action from 3 specific pathophysiologic factors (endothelial dysfunction, oxidative stress and fibrosis) by measuring nitric oxide signaling pathway, NADPH oxidase, TGF-β1 and other factors. Further, we will evaluate the erectile function of rats in response to cavernous nerve stimulation, for identifying the therapeutic possibilities of targeting ACE2/Ang-(1-7)/Mas axis to diabetic ED. Finally, we believe our proposed research is likely to provide new insight regarding the pathogenesis of diabetic ED and thereby reveal novel therapeutic possibilities for the treatment of this disease.

糖尿病性阴茎勃起功能障碍（DED）发病机制复杂，治疗棘手，肾素-血管紧张素系统（RAS）异常激活是其主要发病机制之一。血管紧张素Ang-(1-7)及其合成酶ACE2、特异性受体Mas是RAS中新发现的另一重要信号通路，我们的前期研究结果发现ACE2在DED大鼠阴茎内表达减少，激活ACE2可显著改善阴茎纤维化情况，提示ACE2/Ang-(1-7)/Mas轴可能在DED发病中起到重要作用，但其作用机制有待进一步研究。本研究拟采用DED大鼠模型和海绵体平滑肌、内皮细胞为主要研究对象，药物体内外干预ACE2/Ang-(1-7)/Mas轴，应用分子生物学技术和阴茎海绵体测压技术（评估阴茎勃起功能），从内皮功能紊乱、氧化应激、纤维化三个方面探讨该轴及其调控的下游信号通路在DED发病中的具体作用机制，并评估靶向该轴治疗糖尿病性ED的可行性，为寻找治疗DED的新靶点提供科学实验依据。

男性勃起功能障碍（ED）是威胁男性健康的常见疾病，严重影响生活质量。85%的糖尿病男性患者存在不同程度的ED，且糖尿病性勃起功能障碍（DED）发病机制复杂，治疗效果不佳，肾素-血管紧张素系统（RAS）异常激活是其主要发病机制之一。血管紧张素Ang-(1-7)及其合成酶ACE2、特异性受体Mas是RAS中新发现的另一重要信号通路。前期研究提示ACE2/Ang-(1-7)/Mas轴可能在DED发病中起到重要作用，但其具体作用机制尚不清楚。本研究采用DED大鼠模型和海绵体平滑肌、内皮细胞为主要研究对象，药物体内外干预ACE2/Ang-(1-7)/Mas轴，应用分子生物学技术和阴茎海绵体测压技术（评估阴茎勃起功能），从内皮功能紊乱、氧化应激、纤维化三个方面探讨该轴及其调控的下游信号通路在DED发病中的具体作用机制。结果发现，DED大鼠阴茎内ACE2/Ang-(1-7)/Mas轴受损导致内皮细胞功能受损，氧化应激水平增高，阴茎纤维化发生。而靶向ACE2/Ang-(1-7)/Mas轴，可有效改善DED大鼠勃起功能，其机制可能是通过激活ACE2，降低NADPH氧化酶表达改善氧化应激水平，上调eNOS和nNOS表达水平提高NO生物活性，抑制TGF-β减少阴茎纤维化发生。本研究进一步阐明了ACE2/Ang-(1-7)/Mas轴在DED发病中的具体作用机制，为寻找治疗糖尿病性ED的新靶点提供实验依据。