CHAPERONE FUNCTION AND VASCULAR AGING

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。对细胞应激的易感性增加和血管组织损伤的累积可能是衰老导致动脉粥样硬化环境的因素，但导致动脉粥样硬化病变形成的年龄相关事件的精确分子过程仍有待确定。

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.