Lipidation and Vascular Disease

项目总结/摘要 外周动脉疾病，比冠心病或中风更普遍，往往被忽视。的 疾病随着人口老龄化和糖尿病的流行而增加，但治疗选择 有限公司与冠心病不同，外周动脉疾病并不总是与危险因素相关 如脂蛋白和高血压，它似乎更普遍，更具有临床侵略性， 女性与男性相比。 慢性血管不成熟是外周动脉疾病的特征。脂肪酸代谢影响 脂肪酸棕榈酸酯具有多种功能，包括蛋白质， 脂化棕榈酰化随后脱棕榈酰化的连续循环对于膜运输至关重要。 我们产生了一个缺乏内皮酰基蛋白硫酯酶1（APT 1）的小鼠，APT 1是内皮细胞的主要酶， 逆转蛋白质棕榈酰化。该动物是人类外周动脉疾病的模型。棕榈酰化R- 由APT 1缺乏引起的Ras在这些动物的血管系统中积累，并且R-Ras的表达在这些动物的血管系统中增加。 Ras分子被改造以恢复细胞内运输，挽救生理缺陷。APT 1降低 酶活性和棕榈酰化R-Ras增加。 患有糖尿病和外周动脉疾病的人的下肢动脉具有显著的 与对照动脉相比，棕榈酰化R-Ras含量更高（反映APT 1活性受损） 无血管疾病的非糖尿病患者。APT 1似乎在女性中具有不成比例的影响， 与雄性小鼠相比，患有外周动脉疾病的女性的血管组织 棕榈酰化R-Ras的含量显著更高（反映APT 1活性降低）， 来自患有外周动脉疾病的男性的血管。为了继续观察，我们将测试 假设脱棕榈酰化酶酰基蛋白硫酯酶1（APT 1）缺乏促进 外周动脉疾病我们的具体目标是：1）确定是否增加APT 1酶活性， 药理学和遗传学方法减少小鼠的外周动脉疾病。2)为了确定性别 对APT 1酶活性及其下游靶点R-Ras的特异性作用有助于增加外周血淋巴细胞增殖。 小鼠的动脉疾病。3)为了将这项工作转化为人类， APT 1酶活性、棕榈酰化R-Ras的积累和纤连蛋白加工的改变， 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一个新的靶点， 深入了解性别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.