Summary Acute ischemic injury, such as myocardial infarction (MI), is a major contributor toward the development of heart failure (HF), a progressive disease affecting millions of patients and costing billions of dollars annually. Myeloid cells, such as neutrophils, monocytes and macrophages, are rapidly recruited to (peripheral blood leukocytes, PBL) or activated within (tissue resident macrophages, TRM) the heart following acute injury or stress where they regulate a wide variety of cardiac remodeling responses. Additionally, macrophages secrete numerous paracrine factors to influence their surroundings such as extracellular vesicles (EVs), which includes small 40- 150 nm EVs termed exosomes. We previously demonstrated that the β2-adrenergic receptor (β2AR) is a critical regulator of immune cell responsiveness to cardiac injury, but with limited mechanistic insight, particularly with respect to myeloid cells, including macrophages. We have thus focused on defining the impact of β2AR deletion specifically in myeloid cells on cardiac function and remodeling following injury. We have developed a mouse model with myeloid cell-specific constitutive β2AR deletion (LysM-Cre/β2ARf/f; LB2), which exhibit less maladaptive remodeling following MI, including reduced expansion of dead cardiomyocytes and increased neutrophil clearance, resulting in preservation of cardiac function and reduced fibrotic remodeling. Various myeloid cells isolated from LB2 mice, and PBL from human HF patients chronically taking β-blockers, were found to express higher levels of genes involved in the regulation efferocytosis/phagocytosis, which are known to functionally enhance apoptotic cell clearance and promote cardiac repair. Additionally, exosomes isolated from β2AR-defcient BMDMs contain less inflammatory and more pro-angiogenic factors and induced greater endothelial cell capillary tube formation in vitro. When injected intramyocardially at the time of MI in wild-type mice, β2AR-deficient BMDM-derived exosomes stabilized cardiac function as compared to PBS- or WT exosome-injected mice, which was associated with decreased fibrosis and improved capillary density. Overall, we hypothesize that β2AR deletion results in alterations within myeloid cells, including macrophages and their exosomes, that promote beneficial cardiac remodeling responses following injury. In Aim 1 we will determine the mechanisms by which myeloid cell-specific β2AR deletion enhances cardiac repair following injury, with a focus on efferocytosis and cardiac TRM. In Aim 2 we will investigate whether clinically used β-blockers induce comparative alterations in both PBL and cardiac TRM and if these changes are observed in the PBL of human HF patients. In Aim 3 we will characterize the properties of β2AR-deficient macrophage-derived exosomes that promote angiogenesis and stabilize cardiac remodeling. Overall, the goal of this project is to define how myeloid cell-expressed β2AR regulates cardiac function and...