GLYCINE AND N-ACETYL CYSTEINE SUPPLEMENTED DIET IMPROVES INFLAMMATORY-BASED FIBROSIS IN THE AGING HEART

补充甘氨酸和 N-乙酰半胱氨酸的饮食可改善衰老心脏中的炎症性纤维化

• 批准号: 10284824
• 负责人: KATARZYNA A. CIESLIK
• 金额: $ 16万
• 依托单位: BAYLOR COLLEGE OF MEDICINE
• 依托单位国家: 美国
• 财政年份: 2018
• 资助国家: 美国
• 起止时间: 2018-09-30 至 2022-05-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10284824
• 关键词: Age; Aging; Antioxidants; Attenuated; Binding; Blood Flow Velocity; Blood Vessels; CCL2 gene; CD209 gene; Cardiac; Cells; Chemotactic Factors; Collagen; Cysteine; Data; Dendritic Cells; Deposition; Diet; Dietary Supplementation; EFRAC; Echocardiography; Elderly; Exercise; Failure; Female; Fibroblasts; Fibrosis; Flow Cytometry; Functional disorder; Funding; Glutamic Acid; Glutathione; Glycine; Heart; Heart failure; Human; Individual; Infiltration; Inflammation; Inflammatory; Interleukin-10; Interleukin-6; Intervention; Investigation; Left; Leukocytes; Ligands; Link; Longitudinal Studies; Lymphocyte; Lymphocyte antigen CD50; Metabolic; Metabolism; Mission; Mitochondria; Modeling; Molecular; Mononuclear Leukocytes; Mus; Myocardial dysfunction; Myocarditis; Nature; Pathologic; Pathway interactions; Performance; Pharmacological Treatment; Physiological; Population; Process; Production; Protein Array; Public Health; Reactive Oxygen Species; Reduced Glutathione; Request for Applications; Research; Risk; Role; Sex Differences; Supplementation; Tissues; Ventricular; Woman; Work; aged; base; coronary fibrosis; cytokine; dietary; dietary supplements; endurance exercise; heart function; improved; innovation; interstitial; macrophage; male; monocyte; mouse model; older women; preservation; prevent; receptor; response; sex

PROJECT SUMMARY The US population is aging; in a decade, 20% of people living in the US will be 65 or older. The focus of our work is on the mechanism(s) of improving diastolic dysfunction, reducing cardiac fibrosis and inflammation in mice treated with GlyNAC (glycine + N-Acetyl-Cysteine) with or without DCSL1 (Dendritic Cell-Specific Intercellular Adhesion Molecule 3-Grabbing Non-integrin ligand 1). Our overall objective is to examine functional cardiac and cellular changes in these potential rescue approaches to reduce diastolic dysfunction and cardiac fibrosis in the aging heart. The central hypothesis arose from our data in which we demonstrated that reactive oxygen species and inflammation contribute to the cardiac decline via an inflammatory dependent activation of cardiac fibrosis. We found that an increased level of MCP-1, a leukocyte chemoattractant, causes elevated leukocyte infiltration. Infiltrating monocytes polarize into pro- and anti-fibrotic macrophages, which further contribute to pathological fibroblast activation and excessive collagen production. We found a significant improvement in cardiac function accompanied by reduced fibrosis in aged mice via restoring reduced glutathione (GSH) levels (by treating mice with GlyNAC, glycine and N-acetyl cysteine = glutathione precursors) or by reducing macrophage polarization (via DCSL1). However, we only treated male mice with GlyNAC despite the fact that females display worse diastolic dysfunction and more severe fibrosis than males. Interestingly, DCSL1 treatment, which we applied to both male and female mice, only improved female heart function. Therefore, we postulated that the treatment of male and female aged mice with GlyNAC with or without DCSL1 may prevent or even reverse inflammatory dysfunction and fibrosis in the heart. In SA1, we will determine the effect of the dietary and pharmacological treatment on heart function. Specifically, we will examine vascular function, echocardiography, mitral and aortic blood flow velocities, exercise endurance, invasive systolic, and diastolic functions. In SA2, we will investigate the cellular and molecular mechanisms of the GlyNAC and DCSL1 treatments. At termination, in each mouse, we will analyze macrophage and lymphocyte polarization via flow cytometry and identify cytokines secreted by them via protein array. Finally, collagen deposition and fibrosis will be examined. This approach is innovative and significant because it will allow us to correlate changes in cardiac function to molecular and cellular responses. Furthermore, our Preliminary Data shows a correlation of the mouse model with the human aging heart.

PROJECT SUMMARY The US population is aging; in a decade, 20% of people living in the US will be 65 or older. The focus of our work is on the mechanism(s) of improving diastolic dysfunction, reducing cardiac fibrosis and inflammation in mice treated with GlyNAC (glycine + N-Acetyl-Cysteine) with or without DCSL1 (Dendritic Cell-Specific Intercellular Adhesion Molecule 3-Grabbing Non-integrin ligand 1). Our overall objective is to examine functional cardiac and cellular changes in these potential rescue approaches to reduce diastolic dysfunction and cardiac fibrosis in the aging heart. The central hypothesis arose from our data in which we demonstrated that reactive oxygen species and inflammation contribute to the cardiac decline via an inflammatory dependent activation of cardiac fibrosis. We found that an increased level of MCP-1, a leukocyte chemoattractant, causes elevated leukocyte infiltration. Infiltrating monocytes polarize into pro- and anti-fibrotic macrophages, which further contribute to pathological fibroblast activation and excessive collagen production. We found a significant improvement in cardiac function accompanied by reduced fibrosis in aged mice via restoring reduced glutathione (GSH) levels (by treating mice with GlyNAC, glycine and N-acetyl cysteine = glutathione precursors) or by reducing macrophage polarization (via DCSL1). However, we only treated male mice with GlyNAC despite the fact that females display worse diastolic dysfunction and more severe fibrosis than males. Interestingly, DCSL1 treatment, which we applied to both male and female mice, only improved female heart function. Therefore, we postulated that the treatment of male and female aged mice with GlyNAC with or without DCSL1 may prevent or even reverse inflammatory dysfunction and fibrosis in the heart. In SA1, we will determine the effect of the dietary and pharmacological treatment on heart function. Specifically, we will examine vascular function, echocardiography, mitral and aortic blood flow velocities, exercise endurance, invasive systolic, and diastolic functions. In SA2, we will investigate the cellular and molecular mechanisms of the GlyNAC and DCSL1 treatments. At termination, in each mouse, we will analyze macrophage and lymphocyte polarization via flow cytometry and identify cytokines secreted by them via protein array. Finally, collagen deposition and fibrosis will be examined. This approach is innovative and significant because it will allow us to correlate changes in cardiac function to molecular and cellular responses. Furthermore, our Preliminary Data shows a correlation of the mouse model with the human aging heart.