Abstract P3082: Loss Of Myeloid Cell-specific Beta2-adrenergic Receptor Improves Cardiac Function After Acute Ischemia

Abstract

Heart failure (HF) is one of the leading causes of global mortality, which is often caused by acute myocardial infarction (MI). This type of acute cardiac injury promotes robust inflammatory cascades by regulating spatiotemporal myeloid cell (neutrophil, monocyte and macrophage) responses in the infarct area, which are essential in the orchestration of post-infarct tissue remodeling and repair. We previously reported that deletion of β2-adrenergic receptor (β2AR) in all cells of hematopoietic origin resulted in generalized disruption of immune cell responsiveness to injury, but with unknown impact of myeloid cells in particular. To investigate this, we crossed floxed β2AR (β2 f/f ) mice with myeloid cell-expressing Cre (LysM-Cre) mice to generate myeloid cell-specific β2AR knockout mice (LB2) and subjected them to MI. M-mode echocardiography indicated a preservation of ejection fraction (%EF) and fractional shortening (%FS) in the LB2 mice versus either β2 f/f or LysM-Cre mice at 3 days post-MI, which was maintained at 28 days post-MI, concurrent with reduced infarct size and interstitial fibrosis, suggesting a cardioprotective role of myeloid cell-specific β2-AR deletion. While immune cell profiling by FACS analysis showed similar CD45 + CD11b + Ly6C + monocyte, CD45 + CD11b + Ly6G + neutrophil and CD45 + CD11b + F4/80 + macrophage accumulation in LB2 and β2 f/f mouse hearts at 1 day post-MI, neutrophil frequency was significantly reduced in LB2 mouse hearts by 4 days post-MI, suggesting LB2 hearts have enhanced capacity for efferocytosis of dead cells. Notably, RT-qPCR analysis revealed a significant upregulation of pro-efferocytosis genes in LB2 bone marrow cells, including annexin A1 (ANXA1). Additionally, ANXA1 protein expression was shown to be upregulated in LB2 versus β2 f/f cardiac CD11b + myeloid cells, including macrophages, at 1-day post-MI. In vitro efferocytosis assay data suggested that there was significant increment in %-efferocytosis of LB2 neutrophils as compared to β2 f/f . Taken together, our data suggest that β2AR is a crucial regulator of myeloid cell-dependent efferocytosis in the heart following injury and suggests a crucial timepoint at which β2AR-selective therapeutics may promote the clearance of dead cells to promote repair.