Aging, Stress and Atherosclerosis

冠状动脉疾病的患病率随着年龄的增长而增加，年龄本身是动脉粥样硬化的独立危险因素。活性氧（ROS）和氧化损伤的累积可能是衰老导致动脉粥样硬化环境的因素，但与年龄相关的动脉粥样硬化病变形成中的分子病变仍有待确定。我们最近的数据表明，小鼠为理解衰老对血管壁生物学的内在影响提供了一个很好的模型，这可能有助于我们理解动脉粥样硬化过程。此外，我们一直在体外和体内小鼠模型中探索ROS生成、血管细胞表型和动脉粥样硬化病变形成之间的关系。在确定了SMCs中衰老、ROS产生和动脉粥样硬化病变形成之间的关联之后，我们现在将开始探索将这些过程联系起来的分子事件。为此，我们提出了五个目标：具体目标1-量化ApoE（-/-）背景下ROS生成增加和减少对动脉粥样硬化易感小鼠血管表型的影响；特定目标2-使用我们开发的从小鼠主动脉分离SMCs的新方法，研究具有ROS代谢改变的衰老SMCs中激活的增殖表型和信号通路。我们将确定改变的ROS生成如何影响SMC信号事件的发生和进展以及与衰老相关的增殖变化；具体目标3-通过探索介导年轻小鼠和老年小鼠获得的SMCs之间增殖差异的分子事件，确定老年小鼠SMCs细胞周期进入减弱的机制，重点关注我们所知道的参与SMCs增殖反应的信号和转录事件；具体目标4-确定除抗氧化剂外，保护系统的变化是否有助于老年小鼠的血管细胞表型。特别是，我们将检查分子伴侣在不同背景和年龄的小鼠中的表达，我们将确定分子伴侣的调节如何改变SMC老化和氧化挑战；特异性目标5-表征衰老小鼠SMCs的ROS依赖性和ROS非依赖性转录谱，并与缺乏ROS代谢能力的SMCs的基因表达模式进行比较。基于这些研究，我们将创建与衰老优先相关的ros依赖和ros独立转录物的分子图谱。

The prevalence of coronary artery disease increases with age, and age itself is an independent risk factor for atherogenesis. Reactive oxygen species (ROS) and accrual of oxidative damage are likely factors in the atherogenic milieu attributable to aging, yet the molecular lesions in age- associated atherosclerotic lesion formation remain to be determined. Our recent data indicate that mice provide an excellent model for understanding the intrinsic effects of aging on vascular wall biology that may contribute to our understanding of the atherogenic process. In addition, we have been exploring the relationship between ROS generation, vascular cell phenotypes, and atherosclerotic lesion formation using in vitro and in vivo mouse models. Having established an association between aging, ROS production, and atherosclerotic lesion formation in SMCs, we will now begin to explore the molecular events that link these processes in the present proposal. To do this, we propose five aims: Specific aim number 1- Quantify the impact of increased and decreased ROS production on the vascular phenotypes of aged atherosclerosis-prone mice on the ApoE (-/-) background; Specific aim number 2- Examine the proliferative phenotypes and signaling pathways activated in aged SMCs with altered ROS metabolism using novel methods we have developed to isolate SMCs from mouse aortas. We will determine how altered ROS generation affects the development and progression of SMC signaling events and proliferative changes associated with aging; Specific aim number 3- Determine the mechanism(s) whereby cell cycle entry is attenuated in SMCs from aged mice by exploring the molecular events that mediate the disparity in proliferation we have observed between SMCs obtained from young and old mice, with a focus on signaling and transcriptional events we know to participate in the proliferative response of SMCs; Specific aim number 4- Establish whether changes in protective systems in addition to antioxidants contribute to vascular cell phenotypes of aged mice. In particular, we will examine the expression of molecular chaperones in mice of different backgrounds and ages, and we will determine how SMC aging and oxidative challenges are modified by regulators of molecular chaperones; Specific aim number 5- Characterize the ROS-dependent and ROS-independent transcriptional profiles of SMCs from aged mice in comparison with gene expression patterns of SMCs deficient in their ability to metabolize ROS. Based on these studies, we will create molecular portraits of the ROS-dependent and ROS-independent transcripts preferentially associated with aging.