Reversing Arterial Aging via mTOR Inhibition: AMPK Activation as a Rapalog

描述(申请人提供)：心血管疾病(CVD)是美国主要的死亡原因。衰老是CVD发生的主要危险因素。与年龄相关的主要动脉表型，被认为是导致老年人心血管疾病发展的原因，主要是内皮功能降低和大动脉僵硬增强。最近，研究表明，通过雷帕霉素或基因操作抑制mTOR信号通路可以延长寿命，减少与年龄相关的生理功能障碍。建议的研究旨在确定(A)mTOR信号的增加是否与年龄相关的动脉功能障碍有关，以及(B)饮食中雷帕霉素的治疗和AMPK的激活是否可以逆转年龄相关的动脉功能障碍。我们实验室进行的初步研究表明，动脉mTOR的激活随着年龄的增加而增加，这与年龄相关的内皮功能障碍和大动脉硬化是已知的氧化应激和炎症增加的结果。此外，用mTOR抑制剂雷帕霉素对老年小鼠进行饮食治疗，可以逆转这种与年龄相关的动脉表型，并改善动脉功能。在本应用中，我们将利用饮食中的雷帕霉素治疗，直接评估mTOR在调节转录因子活性和下游基因/蛋白表达方面所起的作用，以及随后对动脉表型和功能的影响。此外，我们将确定AICAR对AMPK的药理激活是否会起到类似于雷帕霉素诱导的mTOR抑制对动脉功能和表型的影响的“Rapalog”的作用。

DESCRIPTION (provided by applicant): Cardiovascular disease (CVD) is the leading cause of death in the United States. Aging is the major risk factor for development of CVD. The major age-related arterial phenotypes, which are thought to be responsible for the development of CVD in older adults, are reduced endothelial function and enhanced large artery stiffness. Recently, it has been demonstrated that inhibition of the mTOR signaling pathway, via rapamycin or genetic manipulation, extends lifespan and reduces age-related physiological dysfunction. The proposed studies aim to determine (a) if increased mTOR signaling is responsible for age-related arterial dysfunction and (b) whether dietary rapamycin treatment and activation of AMPK, a putative "rapalog", can reverse age-related arterial dysfunction. Our laboratory has performed preliminary studies suggesting that arterial activation of mTOR is increased with advancing age and that this is concomitant with age-associated endothelial dysfunction and large artery stiffening known to result from increases in oxidative stress and inflammation. Furthermore, dietary treatment of old mice with mTOR inhibitor, rapamycin, can reverse this age-associated arterial phenotype and improve arterial function. In the present application, by utilizing dietary rapamycin treatment, we will directly assess the role that mTOR plays in modulating transcription factor activity and downstream gene/protein expression and the subsequent effects on arterial phenotype and function. In addition, we will determine if pharmacological activation of AMPK by AICAR will act as a "rapalog," mimicking the effects of rapamycin-induced mTOR inhibition on arterial function and phenotype.