The mTORCI-miR-29-AT2R axis in cardiovascular diseases

心血管疾病中的 mTORCI-miR-29-AT2R 轴

• 批准号: 8484115
• 负责人: Lakshmidevi Pulakat
• 金额: $ 35.54万
• 依托单位: UNIVERSITY OF MISSOURI-COLUMBIA
• 依托单位国家: 美国
• 财政年份: 2013
• 资助国家: 美国
• 起止时间: 2013-07-03 至 2018-04-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8484115
• 关键词: Agonist; Angiotensin II Receptor; Anti-Inflammatory Agents; Anti-inflammatory; Attenuated; Blood Vessels; Cardiovascular Diseases; Cardiovascular Physiology; Cardiovascular system; Cause of Death; Cessation of life; Chronic; Complement; Complex; Computer Simulation; Data; Dexamethasone; Diabetes Mellitus; Disease; Epidemic; Equilibrium; Funding; Growth; Human; Hyperinsulinism; In Vitro; Individual; Inflammation; Insulin Resistance; Investigation; Literature; Mediating; Metabolic; Metabolic syndrome; MicroRNAs; Modeling; Nutrient; Obesity; Outcome; Overweight; Pathway interactions; Patients; Pharmaceutical Preparations; Pharmacologic Substance; Phosphotransferases; Prevalence; Protective Agents; Rattus; Renin-Angiotensin System; Rodent Model; Serum; Sirolimus; Stents; Testing; Tissues; United States; Up-Regulation; Vasodilation; base; combat; diabetic; human FRAP1 protein; improved; innovation; insulin signaling; member; mortality; new therapeutic target; novel; novel therapeutics; nutrition; prevent; public health relevance; response; restenosis; sensor; standard of care

DESCRIPTION (provided by applicant): Prevalence of over-nutrition and metabolic syndrome (MetS) drive the epidemic of cardiovascular disease (CVD), the leading cause of death in the United States. Insulin (INS) resistance that underlies MetS exacerbates vascular complications, cardiovascular remodeling, and CVD associated mortality. The standard of care for the treatment of CVD involves extensive use of anti-inflammatory drugs such as rapamycin (Rap) to prevent vascular restenosis and dexamethasone (Dexa) to manage inflammation. However, accumulating evidence strongly suggest that chronic Rap/Dexa treatments further exacerbate INS resistance in conditions of MetS. Exact mechanism for Rap/Dexa-induced INS resistance is currently unclear. Both Rap and Dexa inhibit mTOR Complex 1 (mTORC1), a nutrient sensor kinase activated in conditions of over-nutrition and MetS and implicated in INS resistance. It is a conundrum that Rap/Dexa increase INS resistance despite inhibiting mTORC1. The basis of this proposal is our unprecedented observation that mTORC1 suppresses the microRNA miR-29 that in turn inhibits the Angiotensin II (Ang II) receptor AT2R, a cardiovascular (CV) protective molecule. The miR-29 induces INS resistance and is up-regulated in tissues and serum of diabetic rodent models and humans. Our in silico and in vitro studies showed that miR-29 suppresses AT2R. Thereby, we hypothesize that mTORC1 activation in conditions of over-nutrition increases AT2R expression as a CV protective mechanism via suppression of miR-29. Since activation of the AT2R induces vasodilatation and inhibits excessive growth, we further hypothesize that activation of the AT2R offers CV protection in MetS. Our conceptually novel hypothesis derived based on our preliminary data and evidence from literature is that Rap and Dexa increase expression of miR-29 that exacerbates INS resistance in CV tissues and attenuates AT2R-mediated CV protection in conditions of MetS. Furthermore, we propose that a novel AT2R agonist, Novokinin (Nov), that regulates mTOR without increasing miR-29 in CV tissues would be an ideal drug to regulate INS resistance and promote CV protection in MetS. In Aim 1, we will investigate if Rap or Dexa disrupts mTORC1->miR-29->AT2R axis by increasing miR-29 and suppressing AT2R and exacerbates CVD in rat models of obesity, INS resistance and hyperinsulinemia. In Aim 2 we will determine if Nov restores mTORC1->miR-29->AT2R axis by regulating miR-29 expression and activating the AT2R, and provides enhanced CV protection in rat models of obesity and MetS that are subjected to Rap or Dexa treatments. Results of this integrative and translationally innovative investigation will unveil potential adverse CV outcomes associated with Rap or Dexa treatments in conditions of MetS. Importantly, they will determine the efficacy of a new CV protective drug, Nov, in ameliorating INS resistance and CVD in conditions of Rap/Dexa treatments in MetS. We expect that the results of these studies will have significant translational value since they will have considerabl impact on the standard of care for CVD in MetS.

描述（由申请人提供）：过度营养和代谢综合征（METS）的患病率推动了美国的主要死亡原因心血管疾病（CVD）的流行。胰岛素（INS）耐药性会加剧血管并发症，心血管重塑和CVD相关的死亡率。治疗CVD的护理标准涉及广泛使用抗炎药，例如雷帕霉素（RAP），以防止血管再生毒和地塞米松（DEXA）管理炎症。然而，积累的证据强烈表明，慢性说唱/DEXA治疗进一步加剧了MetS条件下的耐药性。目前尚不清楚RA​​P/DEXA诱导的INS电阻的确切机制。 RAP和DEXA都抑制MTOR复合物1（MTORC1），这是一种在过度营养和MetS条件下激活的营养传感器激酶，并与INS抗性有关。是一个 尽管抑制MTORC1，但RAP/DEXA增加了INS耐药性的难题。该提案的基础是我们前所未有的观察结果，即MTORC1抑制了MicroRNA miR-29，进而抑制了血管紧张素II（ANG II）受体AT2R（一种心血管（CV）保护性分子）。 miR-29诱导INS抗性，并在糖尿病啮齿动物模型和人类的组织和血清中上调。我们的硅和体外研究表明，miR-29抑制了AT2R。因此，我们假设在过度营养条件下MTORC1激活通过抑制miR-29来增加AT2R表达作为CV保护机制。由于AT2R的激活会诱导血管舒张并抑制过度生长，因此我们进一步假设AT2R的激活在MetS中提供了CV保护。我们根据我们的初步数据和文献证据得出的概念上新的假设是，RAP和DEXA增加了miR-29的表达，这加剧了CV组织中的抗性并减弱了AT2R AT2R介导的CV在MetS条件下的CV保护。此外，我们建议一种新型的AT2R激动剂Novokinin（Novokinin（Novokinin）（Novokinin（Nov））调节MTOR而不增加CV组织中miR-29的MTOR将是调节MetS中INS耐药性并促进CV保护的理想药物。在AIM 1中，我们将研究RAP或DEXA是否通过增加miR-29并抑制AT2R和ATACERBATES CVD中的RAP或DEXA是否会破坏MTORC1-> miR-29-> AT2R轴。在AIM 2中，我们将通过调节miR-29表达和激活AT2R来确定NOV是否恢复MTORC1-> miR-29-> AT2R轴，并在接受RAP或DEXA处理的大鼠模型中提供增强的CV保护。这种综合性和翻译创新研究的结果将在MetS条件下公布与RAP或DEXA处理相关的潜在不良CV结果。重要的是，他们将在MetS中RAP/DEXA处理条件下，确定一种新的CV保护药物（NOV）的新CV保护药物的功效。我们预计这些研究的结果将具有显着的翻译价值，因为它们将对MetS中CVD的护理标准产生明显的影响。