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，心血管疾病是美国死亡的主要原因。胰岛素（INS）抵抗是MetS的基础，会加剧血管并发症、心血管重塑和心血管疾病相关死亡率。心血管疾病治疗的标准护理包括广泛使用抗炎药物，如雷帕霉素（Rap）预防血管再狭窄和地塞米松（Dexa）控制炎症。然而，越来越多的证据强烈表明，慢性Rap/Dexa治疗进一步加剧了MetS患者的INS耐药。Rap/ dexa诱导的INS耐药的确切机制目前尚不清楚。Rap和Dexa都抑制mTOR复合物1 (mTORC1)， mTORC1是一种在营养过度和MetS条件下激活的营养传感器激酶，与INS抗性有关。这是一个

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.