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

描述(由申请人提供)：营养过剩和代谢综合征(METS)的流行推动了心血管疾病(CVD)的流行，心血管疾病是美国的主要死亡原因。作为蛋氨酸基础的胰岛素(INS)抵抗会加剧血管并发症、心血管重塑和心血管相关死亡率。治疗心血管疾病的标准护理包括广泛使用抗炎药，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，越来越多的证据有力地表明，慢性Rap/Dexa治疗进一步加剧了蛋氨酸状态下的胰岛素抵抗。Rap/Dexa诱导INS耐药的确切机制目前尚不清楚。Rap和Dexa都抑制mTOR复合体1(MTORC1)，这是一种在营养过剩和蛋氨酸条件下激活的营养感受器激酶，与INS抵抗有关。这是一个 难题是Rap/Dexa在抑制mTORC1的同时增加了INS的耐药性。这一建议的基础是我们前所未有的观察到，mTORC1抑制microRNA miR-29，而microRNA miR-29又抑制血管紧张素II(Ang II)受体AT2R，AT2R是一种心血管保护分子。MiR-29诱导胰岛素抵抗，并在糖尿病啮齿动物模型和人类的组织和血清中上调。我们的体内和体外研究表明miR-29抑制AT2R。因此，我们假设过度营养条件下mTORC1的激活增加了AT2R的表达，这是一种通过抑制miR-29来保护心血管的机制。由于AT2R的激活诱导血管扩张和抑制过度生长，我们进一步假设AT2R的激活在蛋氨酸中提供心血管保护。基于我们的初步数据和文献证据，我们的概念上的新假说是Rap和Dexa增加了miR-29的表达，从而加剧了心血管组织对INS的抵抗，并减弱了AT2R介导的心血管保护作用。此外，我们认为一种新型的AT2R激动剂Novokinin(NOV)可以在不增加miR-29的情况下调节心血管组织中的mTOR，是调节胰岛素抵抗和促进蛋氨酸心血管保护的理想药物。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而扰乱mTORC1-&gt；miR-29-&gt；AT2R轴，并加剧肥胖、胰岛素抵抗和高胰岛素血症大鼠的心血管疾病。在目标2中，我们将确定NOV是否通过调节miR-29的表达和激活AT2R来恢复mTORC1-&gt；miR-29-&gt；AT2R轴，并在接受Rap或Dexa治疗的肥胖和Met大鼠模型中提供增强的CV保护。这项综合性和翻译创新研究的结果将揭示在METS条件下与Rap或Dexa治疗相关的潜在不良心血管后果。重要的是，他们将确定一种新的心血管保护药物NOV在改善MET患者在Rap/Dexa治疗条件下的INS耐药性和CVD方面的有效性。我们预计这些研究的结果将具有显著的翻译价值，因为它们将对MET的心血管疾病护理标准产生相当大的影响。

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.