ERBB2 Targeting Increases Cardiomyocyte β1-Adrenergic Receptor Density

Abstract

Objective: To determine the underlying pathways that promote cardiotoxicity following anti-ERBB2 cancer therapeutics. Background: Epidermal growth factor receptor 2 (EGFR2/ERBB2) is a member of EGFR (ERBB) family represented by ERBB 1 through 4 that either homo- or hetero-dimerize to signal. ERBB2 has constitutively active confirmation but explicitly needs to hetero-dimerize with either ERBB1 or ERBB4 to mediate signaling and cardiac hypertrophy. Less is known about the mechanisms through which ERBB2 mediates the adaptive cardiac hypertrophy given that anti-ERBB2 therapeutics results in cardiac dilation of the otherwise healthy heart. Methods: We generated transgenic (Tg) mice with cardiomyocyte-specific overexpression of microRNA-7 (miRNA-7) that targets ERBB2. Echocardiography, immunohistochemistry and β-adrenergic receptor (βAR) density were assessed upon aging and transverse aortic constriction (TAC). To determine whether inhibition of ERBB2 has similar outcomes, C57Bl/6 mice were administered ERBB2-specific inhibitor AG825. Also, βAR density was assessed in end-stage human heart failure patient samples with Adriamycin cardiotoxicity. Results: Loss in ERBB2 expression due to miRNA-7 targeting or ERRB2 inhibition by AG 825 results in cardiac dilation. Loss of ERBB2 in miRNA-7 Tg mice leads to increased fibrosis post-TAC. Selective significant increase in β1AR density is observed in miRNA-7 Tg mice or in mice following ERBB2 inhibition by AG825 and in the human heart failure patient samples due to Adriamycin cardiotoxicity. Conclusions: Cardiomyocyte ERBB2 expression and function is required for maintaining the normal cardiac function. Targeting ERBB2 leads to selective and significant increase in β1ARs that may promote cardiac dilation and heart failure.