Impact of SGLT-2 Inhibition on the Cardiometabolic Profile of PCOS

多囊卵巢综合征（PCOS）是影响育龄妇女最常见的内分泌疾病。 年龄，困扰着全世界5-20%的女性。它的特点是高雄激素血症和寡- 排卵多囊卵巢综合征与几种心血管危险因素高度共患病，如肥胖，高血压， 胰岛素抵抗和血脂异常。多囊卵巢综合征患者的线粒体功能障碍也很明显， 可能导致PCOS患者白色脂肪组织（WAT）的不健康扩张。虽然确切的病因 PCOS的发病机制尚不清楚，高雄激素血症似乎是PCOS患者心脏代谢的主要介质。 PCOS。有了这些知识差距，PCOS妇女的选择有限， 降低心血管风险因素。由于心血管疾病是女性的头号杀手， 在美国，患有PCOS的女性迫切需要更多的治疗选择。二甲双胍等治疗 血管紧张素II受体阻滞剂已经显示出一些前景，但它们只能治疗部分疾病。之间 这些新的潜在治疗是钠-葡萄糖协同转运蛋白2抑制剂（SGLT 2 i）， 降低2型糖尿病患者血压和心血管死亡率的治疗工具。最近， SGLT 2 i可降低PCOS女性的体重。此外，在胰岛素抵抗小鼠中，SGLT 2 i 脂肪酸氧化标志物增加，尿8-异前列腺素（氧化应激标志物）减少。 因此，需要研究SGLT 2 i治疗PCOS，因为它们可以降低肥胖、血压， 血脂异常和肾损害。为了研究PCOS中的SGLT 2 i，我们的实验室之前 通过植入双氢睾酮丸，表征了PCOS的Sprague道利雌性大鼠模型， 4周大。我们的高雄激素血症雌性（HAF）大鼠模仿PCOS的许多相同特征 女性如排卵过少，伴有肥胖、血压升高、胰岛素抵抗和肾损伤。 我们有令人兴奋的初步数据表明，SGLT 2 i在我们的模型中减少了肥胖，有证据表明， 从血浆瘦素的显著降低改善WAT。我们还发现肾细胞癌基因的表达减少， 血管紧张素转换酶mRNA。这个项目将测试中心假设，药理学 在HAF大鼠中给予SGLT 2 i将通过下调肾内 血管紧张素系统（RAS）和肥胖的关系。这一假设将 在以下特定目的中进行测试：1）为了验证HAF大鼠中雄激素增加SGLT 2的假设 导致RAS激活，导致血压升高和肾功能降低， SGLT 2 i将降低BP并改善肾血流动力学，和2）为了检验HAF大鼠中的假设， 雄激素导致WAT中的线粒体功能障碍，SGLT 2 i将减弱雄激素诱导的线粒体功能障碍。 线粒体功能障碍导致WAT活性的改善。因此，该项目具有重要的临床意义。 在改善大量但得不到充分服务的妇女人口的健康方面具有转化价值。

Polycystic Ovary Syndrome (PCOS) is the most common endocrine disorder affecting women of reproductive age, afflicting between 5-20% of women worldwide. It is characterized by hyperandrogenemia and oligo- ovulation. PCOS is highly co-prevalent with several cardiovascular risk factors such as obesity, hypertension, insulin resistance, and dyslipidemia. Mitochondrial dysfunction in women with PCOS is also apparent which could lead to the unhealthy expansion of white adipose tissue (WAT) seen in PCOS. While the exact etiology of PCOS is unknown, hyperandrogenemia appears to be a major mediator of the cardiometabolic profile of PCOS. With these knowledge gaps, it is unsurprising that there are limited options for women with PCOS to reduce their cardiovascular risk factors. As cardiovascular disease is the number one killer of women in the United States, women with PCOS desperately need more treatment options. Treatments such as metformin and angiotensin II receptor blockers have shown some promise, but they only treat part of the disease. Among these new potential treatments are sodium-glucose co-transporter 2 inhibitors (SGLT2i), an exciting class of therapeutic tools that reduces BP and cardiovascular mortality in patients with type 2 diabetes. Recently, SGLT2i reduced the body weight of women with PCOS. Additionally, in mice with insulin resistance, SGLT2i increased markers of fatty acid oxidation and decreased urinary 8-isoprostane, a marker of oxidative stress. Therefore, SGLT2i need to be investigated for treatment of PCOS as they may reduce obesity, BP, dyslipidemia, and renal injury in this disease. To study SGLT2i in PCOS, our laboratory has previously characterized a Sprague Dawley female rat model of PCOS via implantation of a dihydrotestosterone pellet at four weeks of age. Our hyperandrogenemic female (HAF) rats mimic many of the same features of PCOS women such as oligo-ovulation accompanied by increased adiposity, BP, insulin resistance, and renal injury. We have exciting preliminary data that SGLT2i decreases adiposity in our model, with evidence of functional improvement of WAT from a marked decreased in plasma leptin. We also found reduced expression of renal angiotensin-converting enzyme mRNA. This project will test the central hypothesis that pharmacological administration of SGLT2i in HAF rats will ameliorate both the increase in BP by downregulating the intrarenal renin-angiotensin system (RAS) and obesity by improving mitochondrial function in WAT. This hypothesis will be tested in the following specific aims: 1) To test the hypothesis that in HAF rats, androgens increase SGLT2 that leads to activation of the RAS leading to increased BP and reduced renal function, and administration of an SGLT2i will decrease BP and improve renal hemodynamics, and 2) To test the hypothesis that in HAF rats, androgens cause mitochondrial dysfunction in WAT and that SGLT2i will attenuate androgen-induced mitochondrial dysfunction leading to improvement in WAT activity. Therefore, this project has a critical clinical and translational value in improving the health of a large but underserved population of women.