Immune Mechanisms Regulating Cardiac Remodeling

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Summary Cardiovascular disease is the number cause of death in the United States. Most cardiovascular diseases are associated with an increase in myocardial mass or cardiac hypertrophy. The heart responds to exercise and other stress through an increase in cardiomyocyte in size in order to produce more force and cope with the increased demand. In addition to signaling pathways that are activated within cardiomyocytes, other cellular changes occur in response to cardiac stress. Some of these changes are adaptive but others are maladaptive. Although many therapies are available for heart failure, we are still not able to prevent maladaptive changes in response to stress. Prevention of maladaptive remodeling can lead to the ultimate avoidance of heart failure. We have acquired preliminary data using innovative technologies showing that macrophages and B cells are activated in the early adaptive phase in response to cardiac stress. Our hypothesis is that cardiac resident macrophages promote adaptive, compensatory remodeling during cardiac stress in a process that is regulated by B cells. Based on our preliminary findings, we are proposing to determine the role of macrophages in the early adaptive phase of cardiac remodeling during pathological and physiological stress (Aim 1), investigate the origins and mechanisms of resident macrophage activation during hypertrophy (Aim 2), and identify the mechanisms by which B cells influence macrophage function during cardiac stress (Aim 3). Throughout the proposal we will use innovative techniques, such as single-cell RNA sequencing and advanced imaging strategies, to probe the role of macrophages and B cells in cardiac remodeling. The ultimate goal of the current proposal is to identify a possible adaptive role of macrophage early during the remodeling process. Using these discoveries, future research will focus on developing novel therapeutics to enhance adaptive remodeling and inhibiting maladaptive remodeling. Given the impact of cardiovascular disease on overall health, this proposal holds great promise for reducing the burden of cardiovascular disease on our society.