Ascorbic Acid Function and Metabolism

动脉粥样硬化性心血管疾病仍然是美国男性和Worman的头号杀手， 尤其是有糖尿病、高血压和肾脏疾病的人。自从晚期治疗人类以来 维生素C和维生素E对动脉粥样硬化的分期几乎没有好处，这个项目的目标是这些 在细胞和容易发生动脉粥样硬化的小鼠体内，抗氧化维生素在这个过程的早期阶段。这个 这种方法的理论基础是近50年前的一项证明，即 豚鼠引起的病变与早期人类动脉粥样硬化的病变难以区分。第一个目标是 评价维生素C在动脉粥样硬化三种主要细胞培养模型中的作用 过程：内皮细胞、血管平滑肌细胞和巨噬细胞。虽然抗氧化功能 将讨论维生素C和维生素E的相互作用，重点将放在如何刺激 维生素C合成胶原蛋白影响内皮细胞和平滑肌细胞的增殖和分化， 以及维生素如何改变关键的巨噬细胞功能，因为这些功能与动脉粥样硬化有关。这个 第二个目标是利用载脂蛋白E缺陷的小鼠动脉粥样硬化模型来评估 细胞内维生素C的含量影响动脉粥样硬化病变的进展、严重程度和性质。 实现这一目标的关键是使用缺乏合成维生素C能力的小鼠和缺乏维生素C合成能力的小鼠 维生素的细胞运输。例如，在受到致命辐射的小鼠中使用胎肝细胞移植，它 将有可能测试缺乏维生素C转运的巨噬细胞中是否存在选择性维生素C缺乏 会加重动脉粥样硬化的进程。在第三个目标中，从这些动物中制备的巨噬细胞将被 培养并用于确定不同细胞内维生素C浓度对巨噬细胞的作用 功能，以及抗氧化剂与维生素E的相互作用，通过关注细胞模型和 在动物模型中，这个项目将展示维生素C是否以及如何预防动脉粥样硬化。

Atherosclerotic cardiovascular disease remains the leading killer of men and wormen in the United States, especially in persons with diabetes, hypertension, and renal disease. Since treating humans in the late stages of atherosclerosis with vitamins C and E shows little benefit, this project targets the role of these antioxidant vitamins in the early stages of the process in cells and in mice prone to atherosclerosis. The rationale for this approach is the demonstration almost 50 years ago that moderate vitamin C deficiency in guinea pigs causes lesions indistinguishable from those of early human atherosclerosis. The first aim will evaluate vitamin C function in cell culture models of the three main cells involved in the atherosclerotic process: endothelial cells, vascular smooth muscle cells, and macrophages. Although antioxidant functions of vitamin C and interactions with vitamin E will be addressed, emphasis will be placed on how stimulation of collagen synthesis by vitamin C affects endothelial and smooth muscle cell proliferation and differentiation, and on how the vitamin can modify key macrophage functions as these relate to atherosclerosis. The second aim will utilize the ApoE-deficient mouse model of atherosclerosisto assess whether varying amounts intracellular vitamin C affect the progression, severity, and nature of the atherosclerotic lesions. Key to this aim is the use of mice that lack the ability to synthesize vitamin C in concert with mice that lack cellular transport of the vitamin. For example, using fetal liver cell transplants in lethally irradiated mice, it will be possible to test whether selective deficiency of vitamin C in macrophages lacking vitamin C transport worsens the atherosclerotic process. In the third aim, macrophages prepared from these animals will be cultured and used to define the role of differing intracellular vitamin C concentrations on macrophage function, and on antioxidant interactions with vitamin E. By focusing on mechanisms in cell models and on early disease in animal models, this project will show whether and how vitamin C prevents atherosclerosis.