Grant Abstract: Glycine and N-Acetyl Cysteine Supplemented Diet Improves Inflammatory-Based Fibrosis in the Aging Heart

Grant Number: 3R01AG059599-03S1
PI Name: Entman
Project Title: Glycine and N-Acetyl Cysteine Supplemented Diet Improves Inflammatory-Based Fibrosis in the Aging Heart

Abstract: 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. PUBLIC HEALTH RELEVANCE: The proposed research is relevant to public health because of the identification of molecular and cellular changes that are associated with inflammation-driven fibrosis in the aging heart. The proposed application is relevant to the part of NIA's mission that relates to the understanding of the nature of aging and aging processes.

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