CHAPERONE FUNCTION AND VASCULAR AGING

冠状动脉疾病的患病率随着年龄的增加而增加，而年龄本身是动脉粥样硬化形成的独立危险因素。细胞应激敏感性的增加和血管组织损伤的增加可能是衰老导致动脉粥样硬化环境的因素，然而，导致动脉粥样硬化病变形成的与年龄相关的事件背后的确切分子过程仍有待确定。 我们最近的数据表明，小鼠为了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，这些影响有助于动脉粥样硬化的形成。我们也开始考虑细胞伴侣机制在细胞应激反应中的一般作用，特别是这些事件可能与动脉粥样硬化病变的形成有关。特别是，我们最近克隆并鉴定了一种新的辅助伴侣/泛素连接酶CHIP(Hsc70相互作用蛋白的羧基末端)，并发现该蛋白通过激活关键的应激调节转录因子HSF1在平衡蛋白质折叠和降解以及调节应激反应中发挥着令人惊讶的中心作用。AS 为了证明CHIP在与血管老化相关的应激反应事件中发挥核心作用，我们产生了缺乏CHIP的小鼠，这些小鼠的应激反应受损，许多特征与加速老化一致。我们现在将开始探索将本提案中的这些过程联系在一起的分子事件。为此，我们提出了四个目标：特定目标#1--确定CHIP缺乏对衰老相关表型的影响；特定目标#2--在体外建立CHIP缺乏对血管平滑肌细胞的细胞影响；特定目标#3--确定细胞应激调节对血管表型和体内动脉粥样硬化形成的作用；特定目标#4--研究伴侣蛋白的相互作用 具有氧化代谢和IGF-1信号的系统。这些研究将描绘伴侣功能障碍、慢性氧化损伤和决定血管对衰老反应的IGF-1信号变化之间的相互作用。

The prevalence of coronary artery disease increases with age, and age itself is an independent risk factor for atherogenesis. Increased susceptibility to cellular stress and accrual of damage to vascular tissues are likely factors in the atherogenic milieu attributable to aging, yet the precise molecular processes underlying the age-associated events culminating in 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 contribute to the atherogenic process. We have also begun to consider the general role of the cellular chaperone machinery in the cell stress response, particularly as these events may be relevant to atherosclerotic lesion formation. In particular, we have recently cloned and characterized a novel co-chaperone/ubiquitin ligase, CHIP (carboxyl terminus of Hsc70-interacting protein), and have identified a surprising central role for this protein in balancing protein folding and degradation and regulating the stress response through its ability to activate the crucial stress-regulatory transcription factor HSF1. As proof that CHIP has a central role in stress-responsive events relevant to vascular aging, we have generated mice deficient in CHIP that have an impaired stress response and many features that are consistent with accelerated aging. We will now begin to explore the molecular events that link these processes in the present proposal. To do this, we propose four aims: Specific aim #1-- Determine the effects of CHIP deficiency on aging-related phenotypes; Specific aim #2-- Establish the cellular consequences of CHIP deficiency in vascular smooth muscle cells in vitro; Specific aim #3-- Determine the role of the cell stress regulation on vascular phenotypes and atherogenesis in vivo; Specific aim #4--- Examine the interactions of the chaperone system with oxidative metabolism and IGF-1 signaling. These studies will create a portrait of the interactions between chaperone dysfunction, chronic oxidative injury, and alterations in IGF-1 signaling that determine the vascular response to aging.