Lipidation and Vascular Disease

脂化和血管疾病

• 批准号: 10602437
• 负责人: Clay F. Semenkovich
• 金额: $ 39.38万
• 依托单位: WASHINGTON UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2021
• 资助国家: 美国
• 起止时间: 2021-04-21 至 2025-03-31
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10602437
• 关键词: Address; Adherens Junction; Affect; Aging; Amputation; Animals; Arteries; Atherosclerosis; Awareness; Biological; Biological Markers; Biology; Blood Vessels; Cardiovascular system; Caring; Cerebrovascular Disorders; Cessation of life; Chronic; Clinical; Coronary heart disease; Defect; Diabetes Mellitus; Disease; Endothelium; Engineering; Enzymes; Epidemic; Event; Fatty Acids; Female; Fibronectins; Fright; Functional disorder; Genetic; Health Care Costs; Hindlimb; Human; Hypertension; Impairment; Individual; Ischemia; Knowledge; Lipoproteins; Lower Extremity; Membrane; Metabolic syndrome; Modeling; Morbidity - disease rate; Mus; Myocardial Infarction; Myocardial Ischemia; Non-Insulin-Dependent Diabetes Mellitus; Palmitates; Patients; Peripheral; Peripheral arterial disease; Persons; Physiologic pulse; Physiological; Population; Post-Translational Protein Processing; Prevalence; Proteins; Proteomics; Public Health; Recovery; Risk; Risk Factors; Stroke; Testing; Therapeutic; Tissues; Translating; United States; Vascular Diseases; Vascular remodeling; Woman; Work; aging population; comparison control; enzyme activity; fatty acid metabolism; genetic approach; human female; human male; human tissue; insight; male; men; mortality; mouse model; neglect; non-diabetic; novel; novel strategies; palmitoylation; pharmacologic; sex; trafficking

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.

项目概要/摘要 外周动脉疾病比冠心病或中风更常见，但常常被忽视。这 随着人口老龄化和糖尿病的流行，疾病正在增加，但治疗选择 有限的。与冠心病不同，外周动脉疾病并不总是与危险因素相关 例如脂蛋白和高血压，它似乎在以下人群中更为普遍且更具临床侵袭性： 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 血管系统的重塑，脂肪酸棕榈酸酯具有多效性功能，包括蛋白质 脂化。棕榈酰化和去棕榈酰化的连续循环对于膜运输至关重要。 我们培育了一只内皮酰蛋白硫酯酶 1 (APT1) 缺陷的小鼠，APT1 是 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 APT1 缺陷引起的 Ras 在这些动物的脉管系统中积聚，并表达 R- 旨在恢复细胞内运输的 Ras 分子可挽救生理缺陷。 APT1 减少 在糖尿病模型中发现酶活性和棕榈酰化 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着的 与对照动脉相比，棕榈酰化 R-Ras 含量更高（反映 APT1 活性受损） 没有血管疾病的非糖尿病人。 APT1 似乎对女性有不成比例的影响 与雄性小鼠相比，患有外周动脉疾病的人类女性的血管组织 与相比，棕榈酰化 R-Ras 的含量显着增加（反映 APT1 活性降低） 来自患有外周动脉疾病的人类男性的血管。为了追求这些观察结果，我们将测试 假设去棕榈酰化酶酰基蛋白硫酯酶 1 (APT1) 缺乏会促进 周围动脉疾病。我们的具体目标是： 1) 确定是否可以通过以下方式增加 APT1 酶活性： 药理学和遗传学方法可减少小鼠外周动脉疾病。 2）判断是否性别 对 APT1 酶活性及其下游靶标 R-Ras 的特定影响有助于增加外周血 小鼠动脉疾病。 3）通过确定减少的后果是否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被忽视的疾病确定新的靶标，并提供 深入了解性和糖尿病如何影响外周动脉疾病。