Project Summary Cardiovascular disease (CVD) is the leading cause of death in the United States. Multiple studies indicate that Post-Traumatic Stress Disorder (PTSD) is a risk factor for CVD. Clinical studies suggest that PTSD stimulates chronic and uncontrolled inflammation through various cytokines and immune cells like macrophages and matrix metalloproteinase (MMP)-9. While these presented studies highlight associations, literature is lacking in mechanisms connecting both CVD and PTSD, leaving patients vulnerable to CVD associated events. Accordingly, the proposed study aims to determine the association between PTSD-induced chronic inflammation and the resetting of cardiac homeostasis. The central hypothesis is that PTSD stimulates recruitment of monocyte-derived macrophages to the heart, resulting in increased cardiac fibrosis and resetting cardiac homeostasis via MMP-9 dependent mechanism. Aim 1 will test the hypothesis that monocyte specific MMP-9 stimulates PTSD-mediated cardiac remodeling and dysfunction. Aim 2 will test the hypothesis that PTSD-induced hyperactivation of monocytes stimulate fibroblast ECM production. Together the data will provide a foundation for future mechanistic studies between CVD and PTSD to further the fields of both cardiology and neuroscience. Collectively, the proposed studies align with the mission of NIH and NHLBI and will enhance overall health, quality of life, and reduce disability.