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

心血管疾病中的 mTORCI-miR-29-AT2R 轴

• 批准号: 8791449
• 负责人: Lakshmidevi Pulakat
• 金额: $ 1.66万
• 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/8791449
• 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; Health; 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; 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）：营养过剩和代谢综合征（MetS）的流行导致心血管疾病（CVD）的流行，心血管疾病是美国的主要死因。胰岛素抵抗是代谢综合征的基础，可加重血管并发症、心血管重塑和CVD相关死亡率。CVD治疗的标准护理涉及广泛使用抗炎药物，如雷帕霉素（Rap）预防血管再狭窄和地塞米松（Dexa）管理炎症。然而，越来越多的证据强烈表明，长期Rap/Dexa治疗进一步加剧了MetS条件下的INS耐药性。Rap/Dexa诱导INS耐药性的确切机制目前尚不清楚。Rap和Dexa均抑制mTOR复合物1（mTORC 1），这是一种在营养过剩和MetS条件下激活的营养传感器激酶，与INS抗性有关。这是一个 Rap/Dexa尽管抑制mTORC 1，但仍增加INS抗性。这一提议的基础是我们前所未有的观察，即mTORC 1抑制microRNA miR-29，进而抑制血管紧张素II（Ang II）受体AT 2 R（一种心血管（CV）保护分子）。miR-29诱导INS抗性，并且在糖尿病啮齿动物模型和人类的组织和血清中上调。我们的计算机模拟和体外研究表明，miR-29抑制AT 2 R。因此，我们假设mTORC 1在营养过剩条件下的激活通过抑制miR-29增加AT 2 R表达作为CV保护机制。由于AT 2 R的激活诱导血管舒张并抑制过度生长，我们进一步假设AT 2 R的激活在MetS中提供CV保护。基于我们的初步数据和文献证据，我们的概念性新假设是Rap和Dexa增加了miR-29的表达，这加剧了CV组织中的INS抗性，并减弱了MetS条件下AT 2 R介导的CV保护。此外，我们提出一种新型AT 2 R激动剂Novokinin（Nov），可调节mTOR而不增加CV组织中的miR-29，将是调节INS抗性并促进MetS中CV保护的理想药物。在目标1中，我们将研究Rap或Dexa是否通过增加miR-29和抑制AT 2 R来破坏mTORC 1->miR-29-> AT 2 R轴，并在肥胖、INS抵抗和高胰岛素血症的大鼠模型中加重CVD。在目标2中，我们将确定Nov是否通过调节miR-29表达和激活AT 2 R来恢复mTORC 1->miR-29-> AT 2 R轴，并在接受Rap或Dexa治疗的肥胖和MetS大鼠模型中提供增强的CV保护。这项综合性和创新性研究的结果将揭示MetS条件下与Rap或Dexa治疗相关的潜在不良CV结局。重要的是，他们将确定一种新的CV保护药物Nov在MetS中Rap/Dexa治疗条件下改善INS抵抗和CVD的疗效。我们预计这些研究的结果将具有重要的转化价值，因为它们将对MetS中CVD的护理标准产生不可估量的影响。