Abstract 423: Cardiomyocyte-Specific Epidermal Growth Factor Receptor Deletion Differentially Alters Cardiac Contractility and Remodeling During Physiologic versus Pathologic Development

Abstract

Epidermal Growth Factor Receptor (EGFR), a member of the Erbb receptor tyrosine kinase family, is essential to the development of multiple tissue and organs. Due to the embryonic lethality of global EGFR deletion, the impact of EGFR signaling in the adult heart, normally or in response to pathological stimuli, has not been well-explored. Using recently attained mice with floxed EGFR alleles crossed with αMHC-Cre mice, we have generated a cardiomyocyte-specific constitutive EGFR knockout mouse model (CM-EGFR KO) to address its role in the heart. Compared to their wild-type (WT) littermate controls, CM-EGFR-KO mice displayed age-related development of cardiac dysfunction and remodeling, occurring between 7 and 9 weeks of age, as monitored via echocardiography and immunohistochemistry analyses. Although contractile responsiveness to β-adrenergic receptor stimulation was unaffected by EGFR deletion, RNASeq analysis of CM-EGFR-KO hearts within this timeframe revealed alterations in myofilament protein expression profiles. Additionally, there was enhanced cardiomyocyte death in the 7-9 week window of development, which persisted to 10 months of age, at which time the CM-EGFR KO mice had progressively worsened cardiac function, dilation and cardiomyocyte loss. To investigate the impact of cardiomyocyte-specific EGFR deletion on the response to pathologic stress, we challenged 12-14 week old WT and CM-EGFR KO mice with chronic isoproterenol infusion. Notably, while chronic isoproterenol treatment diminished cardiac function and induced hypertrophic remodeling in WT mouse hearts, CM-EGFR-KO mouse hearts displayed progressively improved contractility and ablated hypertrophy over time, suggesting that EGFR differentially regulates cardiac function and remodeling processes during physiological versus pathological development.