Myeloid cell-specific β2AR deletion enhances cardiac hypertrophy and alters leukocyte behavior following pressure overload

As part of the sympathetic nervous system, immune cell-expressed β2 adrenergic receptor (β2AR) plays an important role in regulating their responses to cardiac injury. We previously demonstrated that deletion of β2AR in all cells of hematopoietic origin resulted in decreased immune cell recruitment, cardiac repair and survival following acute myocardial infarction, however the impact of myeloid cell-specific β2AR on chronic heart failure (HF)-induced remodeling remain unknown. Thus, we examined the impact of myeloid cell-specific β2AR deletion (Lyz2-Cre x Adrb2fl/fl (LB2) versus Adrb2fl/fl (b2fl) mice) on transaortic constriction (TAC)-induced HF. Despite a similar initial decline in ejection fraction (EF) at 4 weeks post-TAC, LB2 mice displayed a better-preserved EF versus b2fl mice at 8 weeks post-TAC, which reached a comparable level by 16 weeks post-TAC. The temporary improvement of cardiac function in the early stage following TAC may be related to an enhanced compensatory hypertrophy in LB2 mice. Indeed, left ventricle posterior wall thickness was higher in LB2 mice especially in the early stage after TAC (4-8 weeks). This association with enhanced hypertrophy was also observed in an independent model of angiotensin II-infused LB2 versus b2fl mice with higher expression of Nppa and Nppb observed in LB2 hearts. Via flow cytometry, we observed lower levels of total bone marrow-derived leukocytes, inflammatory monocytes, macrophages and neutrophils in the hearts of LB2 versus b2fl mice at 16 weeks post-TAC, whereas total myeloid cells seemed similar between the genotypes. Notably, among the macrophages present in the heart, there was a higher percentage of anti-inflammatory CD206+ (reparative) macrophages in LB2 mice. In conclusion, these results show that myeloid cell-specific β2AR regulates cardiac remodeling during the development of chronic HF, which may occur via modulation of the expansion and phenotypic modulation of distinct myeloid cell populations. © FASEB.