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.

项目总结/文摘