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

SGLT-2 抑制对 PCOS 心脏代谢特征的影响

基本信息

批准号：
10355464
负责人：
Jacob E Pruett
金额：
$ 3.86万
依托单位：
UNIVERSITY OF MISSISSIPPI MED CTR
依托单位国家：
美国
项目类别：
财政年份：
2021
资助国家：
美国
起止时间：
2021-03-01 至 2023-02-28
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/10355464
关键词：
Adipose tissue Affect Age Androgen Receptor Androgens Angiotensin II Angiotensin II Receptor Angiotensinogen Animals Attenuated Blood Glucose Blood Pressure Body Weight Body Weight decreased Body fat Cardiometabolic Disease Cardiovascular Diseases Cardiovascular system Characteristics Clinical Data Disease Dyslipidemias Eating Endocrine System Diseases Etiology Fasting Fatty acid glycerol esters Female Glucose Glucose Transporter Goals Gold Health Homeostasis Hyperandrogenemia Hypertension Imaging Techniques Impairment Infusion procedures Injury to Kidney Insulin Resistance Isoprostanes Kidney Knowledge Laboratories Lead Leptin Light Mediating Mediator of activation protein Messenger RNA Metformin Methods Mitochondria Modeling Mus Nephrons Non-Insulin-Dependent Diabetes Mellitus Obesity Oxidative Stress Patients Peptidyl-Dipeptidase A Pharmacology Physiological Plasma Play Polycystic Ovary Syndrome Prevalence Publishing Rattus Renal Hypertension Renal Tissue Renal function Renin Renin-Angiotensin System Reporting Rodent Role SOD2 gene Sodium Stanolone Testing Therapeutic Therapeutic Agents Tissue Expansion Tubular formation Type 2 diabetic Underserved Population United States Up-Regulation Woman base blood pressure elevation blood pressure reduction blood pressure regulation cardiometabolism cardiovascular risk factor clinically relevant fatty acid oxidation functional improvement hemodynamics implantation improved inhibitor mRNA Expression male mitochondrial dysfunction molecular imaging mortality novel oligo ovulation ovarian dysfunction protein expression reproductive symporter therapeutically effective tool urinary

项目摘要

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.

多囊卵巢综合症（PCOS）是影响生育期女性最常见的内分泌疾病年龄，困扰着全世界 5-20% 的女性。其特点是高雄激素血症和寡雄激素血症。排卵。 PCOS 与多种心血管危险因素高度共存，例如肥胖、高血压、胰岛素抵抗和血脂异常。患有 PCOS 的女性线粒体功能障碍也很明显可能导致多囊卵巢综合症中白色脂肪组织（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 心脏代谢特征的主要调节因素多囊卵巢综合症。由于这些知识差距，患有多囊卵巢综合症的女性选择有限也就不足为奇了。减少心血管危险因素。心血管疾病是女性第一杀手在美国，患有多囊卵巢综合症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受体阻滞剂已显示出一些希望，但它们只能治疗部分疾病。之中这些新的潜在治疗方法是钠-葡萄糖协同转运蛋白 2 抑制剂 (SGLT2i)，这是一类令人兴奋的药物降低 2 型糖尿病患者血压和心血管死亡率的治疗工具。最近， SGLT2i 降低了患有 PCOS 的女性的体重。此外，在具有胰岛素抵抗的小鼠中，SGLT2i 脂肪酸氧化标志物增加，尿中 8-异前列腺素（氧化应激标志物）减少。因此，需要研究 SGLT2i 用于治疗 PCOS，因为它们可以减少肥胖、血压、血脂异常，以及本病的肾损伤。为了研究 PCOS 中的 SGLT2i，我们实验室之前通过植入二氢睾酮颗粒，建立了多囊卵巢综合症 Sprague Dawley 雌性大鼠模型四周龄。我们的高雄激素雌性 (HAF) 大鼠模仿了 PCOS 的许多相同特征女性排卵少，伴有肥胖、血压、胰岛素抵抗和肾损伤。我们有令人兴奋的初步数据表明 SGLT2i 在我们的模型中可以减少肥胖，并有功能性证据血浆瘦素显着下降，WAT 得到改善。我们还发现肾血管紧张素转换酶 mRNA。该项目将测试药理学的中心假设在 HAF 大鼠中给予 SGLT2i 将通过下调肾内血压来改善血压升高通过改善 WAT 中的线粒体功能来抑制肾素-血管紧张素系统 (RAS) 和肥胖。这个假设将在以下具体目标中进行测试： 1) 测试 HAF 大鼠中雄激素增加 SGLT2 的假设导致 RAS 激活，导致血压升高和肾功能降低，以及给予 SGLT2i 将降低血压并改善肾脏血流动力学，2) 检验 HAF 大鼠的假设：雄激素导致 WAT 线粒体功能障碍，SGLT2i 会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 活性改善。因此，本项目具有重要的临床意义以及改善大量但服务不足的女性群体健康的转化价值。