MYELOID SPECIFIC EGFR REGULATES CARDIAC HOMEOSTASIS AND PROTECTS THE INFARCTED HEART DURING REPAIR

Abstract

Background & Rationale: Tissue residing macrophages (TRMs) guard normal physiology in the steady-state heart, and can be important for coordinating inflammatory events at the onset of injuries like myocardial infarction (MI). Following an ischemic attack though, TRMs become outnumbered by circulating myeloid cells and monocyte (mon) derived macrophages (mf), which function to clear injury debris and instruct cardiac repair to mitigate heart failure (HF) severity. The major goal of this work is to investigate how TRM and post MI mf are regulated to participate in cardiac health and post injury repair. Epidermal growth factor receptor (EGFR) is a cell surface tyrosine kinase receptor governing numerous cell processes, and though it has been historically studied as an oncogene, EGFR is implicated in cardiac physiology, and has been shown to regulate mf activation, survival and function. Objectives: Here, we investigated how the loss of EGFR in mf would impact basal cardiac structure, and function, as well as post MI remodeling, repair, and HF development. Methods & Results: By using a myeloid-specific cre, we generated mice with EGFR knockout in mf and other myeloid cells (EGFRmylKO), and performed comparative analyses between these and control mice. We identified that the loss of EGFR in myeloid cells, including cardiac TRMs, resulted in modest signs of stress at baseline, namely enlarged cardiomyocytes and elevated stress associated fetal gene transcripts. Though the loss of EGFR did not impact TRM subtype distribution in basal hearts, whole transcriptomic analyses of these cells revealed over 700 differentially expressed in EGFRmylKO relative to control. Among these are insulin like growth factor (IGF) binding proteins (IGFBP) family members 5 and 7, which are known to regulate not only IGF availability, but also IGF and other cytokine receptor activation, all key players in cardiac hypertrophy. Indeed, EGFRmylKO hearts exhibited enhanced extracellular signal-regulated kinase (ERK)1/2 activation relative to control. Additionally, in response to MI, EGFRmylKO mice experienced a hastened decline in cardiac function, coupled with exacerbated hypertrophic remodeling, and limited angiogenic repair. Analyses of the inflammatory response in EGFRmylKO injured hearts revealed a greater percentage of inflammatory CCR2/Ly6Chi mf even at 7 days into the injury, resulting in significantly reduced transcripts of reparative factors like interleukin (IL)-10. Conclusions: In sum, we propose novel roles for mf EGFR in cardiac physiology and pathology. TRM EGFR regulates several transcripts, required to maintain cardiac homeostatic integrity. In ischemic injury, mf EGFR is key to promoting repair and limiting HF severity.