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）：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原因。 MetS 背后的胰岛素 (INS) 抵抗会加剧血管并发症、心血管重塑和 CVD 相关死亡率。 CVD 治疗的标准护理包括广泛使用抗炎药物，如雷帕霉素 (Rap) 来预防血管再狭窄，以及地塞米松 (Dexa) 来控制炎症。然而，越来越多的证据强烈表明，长期 Rap/Dexa 治疗会进一步加剧 MetS 情况下的 INS 耐药性。 Rap/Dexa 诱导的 INS 抗性的确切机制目前尚不清楚。 Rap 和 Dexa 均抑制 mTOR 复合物 1 (mTORC1)，这是一种营养传感器激酶，在营养过剩和 MetS 条件下激活，与 INS 耐药有关。它是一个 尽管 Rap/Dexa 抑制 mTORC1，但 Rap/Dexa 仍增加 INS 抗性。这一提议的基础是我们前所未有的观察结果，即 mTORC1 抑制 microRNA miR-29，进而抑制血管紧张素 II (Ang II) 受体 AT2R（一种心血管 (CV) 保护分子）。 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。我们的计算机和体外研究表明 miR-29 抑制 AT2R。因此，我们假设营养过剩条件下 mTORC1 的激活会通过抑制 miR-29 来增加 AT2R 的表达，作为一种 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。基于我们的初步数据和文献证据得出的概念性新颖假设是，Rap 和 Dexa 增加 miR-29 的表达，从而加剧 CV 组织中的 INS 抵抗，并减弱 MetS 条件下 AT2R 介导的 CV 保护。此外，我们提出，一种新型 AT2R 激动剂 Novokinin (Nov) 可以在不增加 CV 组织中 miR-29 的情况下调节 mTOR，这将是调节 INS 抵抗并促进 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 AT2R 来破坏 mTORC1->miR-29->AT2R 轴，并加剧肥胖、INS 抵抗和高胰岛素血症大鼠模型中的 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 AT2R 来恢复 mTORC1->miR-29->AT2R 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。这项综合和转化创新研究的结果将揭示与 MetS 条件下 Rap 或 Dexa 治疗相关的潜在不良心血管结果。重要的是，他们将确定新的 CV 保护药物 Nov 在 MetS 的 Rap/Dexa 治疗条件下改善 INS 耐药性和 CVD 的功效。我们预计这些研究的结果将具有重大的转化价值，因为它们将对 MetS 的 CVD 护理标准产生相当大的影响。