Lipidation and Vascular Disease

脂化和血管疾病

• 批准号: 10180573
• 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/10180573
• 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; Health Care Costs; Hindlimb; Human; Hypertension; Impairment; Individual; Ischemia; Knowledge; Lipids; 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; Pharmacology; 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; base; diabetes mellitus genetics; 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; 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.

项目摘要/摘要 通常忽略比冠心病或中风更普遍的周围动脉疾病。这 随着人群的衰老和糖尿病的流行，疾病正在增加，但治疗选择是 有限的。与冠心病不同，周围动脉疾病与危险因素不一致 例如脂蛋白和高血压，似乎更普遍，临床上更具侵略性 与男人相比。 慢性血管不成熟是外周动脉疾病的特征。脂肪酸代谢影响 脉管系统的重塑和脂肪酸棕榈酸酯具有多效性功能，包括蛋白 脂质。棕榈酰化的连续循环随后是去氨木二酰化对于膜运输至关重要。 我们生成了一只具有不足内皮酰基蛋白硫酯酶1（APT1）的小鼠，是主要的酶 逆转蛋白质棕榈酰化。该动物是人类周围动脉疾病的模型。棕榈酰r- 由APT1缺乏引起的RA在这些动物的脉管系统中积累，R-表达 RAS分子设计为恢复细胞内贩运可挽救生理缺陷。减少了APT1 在糖尿病模型中发现酶活性和棕榈酰化的RAS增加。 来自糖尿病和周围动脉疾病的人类的下肢动脉有明显的 与对照组相比，棕榈酰化的R-RAS含量更大 没有血管疾病的非糖尿病人。 APT1在女性中似乎具有不成比例的作用 与雄性小鼠和外周动脉疾病女性的血管组织相比 与 来自男性的血管患有周围动脉疾病。为了追求这些观察，我们将测试 假设deplmitoylation酶酰基蛋白硫酯酶1（APT1）的缺乏促进 周围动脉疾病。我们的具体目的是：1）确定是否通过 药理学和遗传方法可降低小鼠外周动脉疾病。 2）确定是否性 对APT1酶活性及其下游目标R-RAS的特定影响有助于增加周围 小鼠动脉疾病。 3）通过确定减少的后果将这项工作转化为人类 APT1酶活性，棕榈酰化的R-RAS的积累和纤连蛋白加工的改变是 反映在患有周围动脉疾病的男性和男性的动脉中。 实现这些目标有可能确定被忽视疾病的新目标，并提供 深入了解性别和糖尿病如何影响周围动脉疾病。