Lipidation and Vascular Disease

项目摘要/摘要 外周动脉疾病比冠心病或中风更常见，通常被忽视。这个 随着人口老龄化和糖尿病的流行，疾病正在增加，但治疗方案是 有限的。与冠心病不同，外周动脉疾病并不总是与危险因素有关 如脂蛋白和高血压，它似乎更普遍，在临床上更具侵略性 女性与男性相比。 慢性血管不成熟是外周动脉疾病的特征。脂肪酸代谢的影响 血管系统的重塑，脂肪酸棕榈酸酯具有包括蛋白质在内的多功能功能 唇化手术。在膜转运过程中，棕榈酰化和去乙酰化的连续循环是至关重要的。 我们产生了一只内皮酰基蛋白硫酯酶1(APT1)缺陷的小鼠，APT1是 逆转蛋白质棕榈酰化。这种动物是人类外周动脉疾病的模型。棕榈酰化R- 由APT1缺乏引起的RAS在这些动物的血管系统中积聚，并表达一种R- RAS分子被设计用来恢复细胞内的运输，从而挽救了生理缺陷。APT1减少 在糖尿病模型中发现了酶活性和棕榈酰化R-RAS的增加。 糖尿病和外周动脉疾病患者的下肢动脉有显著的 与对照组相比，棕榈酰化R-RAS(反映APT1活性受损)的含量更高 没有糖尿病、没有血管疾病的人。APT1似乎在女性AS中有不成比例的影响 与雄性小鼠相比，患有外周动脉疾病的女性人类血管组织 棕榈酰化R-RAS(反映APT1活性降低)的含量显著高于 来自患有外周动脉疾病的男性的血管。为了继续这些观察，我们将测试 脱氨酶酰基蛋白硫酯酶1(APT1)缺失的假说促进 外周动脉疾病。我们的具体目标是：1)确定通过以下方式提高APT1酶活性 药物和遗传方法可减少小鼠的外周动脉疾病。2)确定性行为是否 APT1酶活性及其下游靶标R-RAS的特异性作用导致外周血细胞增多 小鼠的动脉疾病。3)通过确定减少的后果是否会将这项工作转化为人类 APT1酶活性，棕榈酰化R-RAS的积累和纤维连接蛋白加工的改变，是 反映在患有外周动脉疾病的女性和男性的动脉中。 实现这些目标有可能为一种被忽视的疾病确定新的靶点，并提供 洞察性行为和糖尿病如何影响外周动脉疾病。

Project Summary/Abstract Peripheral artery disease, more prevalent than coronary heart disease or stroke, is often ignored. The disease is increasing with the aging of the population and the epidemic of diabetes, but therapeutic options are limited. Unlike coronary heart disease, peripheral artery disease is not consistently associated with risk factors such as lipoproteins and hypertension, and it appears to be more prevalent and more clinically aggressive in women as compared to men. Chronic vessel immaturity characterizes peripheral artery disease. Fatty acid metabolism impacts remodeling of the vasculature, and the fatty acid palmitate has pleiotropic functions that include protein lipidation. Successive cycles of palmitoylation followed by depalmitoylation are critical for membrane trafficking. We generated a mouse with deficient endothelial acyl-protein thioesterase 1 (APT1), the dominant enzyme for reversing protein palmitoylation. This animal is a model for human peripheral artery disease. Palmitoylated R- Ras, caused by APT1 deficiency, accumulates in the vasculature of these animals, and expression of an R- Ras molecule engineered to restore intracellular trafficking rescues physiologic defects. Decreased APT1 enzyme activity and increased palmitoylated R-Ras are found in diabetes models. Lower extremity arteries from humans with diabetes and peripheral artery disease have a significantly greater content of palmitoylated R-Ras (reflecting impaired APT1 activity) compared to arteries from control nondiabetic humans with no vascular disease. APT1 appears to have a disproportionate effect in female as compared to male mice, and vascular tissue from human females with peripheral artery disease has significantly greater content of palmitoylated R-Ras (reflecting decreased APT1 activity) as compared to vessels from human males with peripheral artery disease. To pursue these observations, we will test the hypothesis that deficiency of the depalmitoylation enzyme acyl-protein thioesterase 1 (APT1) promotes peripheral artery disease. Our specific aims are: 1) To determine if increasing APT1 enzyme activity by pharmacologic and genetic approaches decreases peripheral artery disease in mice. 2) To determine if sex specific effects on APT1 enzyme activity and its downstream target R-Ras contribute to increased peripheral artery disease in mice. 3) To translate this work to humans by determining if the consequences of decreased APT1 enzyme activity, the accumulation of palmitoylated R-Ras and altered fibronectin processing, are reflected in arteries from women and men with peripheral artery disease. Achieving these aims has the potential to identify a novel target for a neglected disease, and to provide insight into how sex and diabetes affect peripheral artery disease.