Cardiomyocyte ErbB4 Receptors Maintain Cardiac Function in Adult Hearts and are Essential for Cardiac Hypertrophy and Growth of Neonatal Mice

Abstract

Activation of ErbB4 by neuregulin 1 (NRG1) promotes cardiomyocyte hypertrophy and proliferation in neonatal and adult mice, whereas application of NRG1 following myocardial infarction reduces scar size and improves function. Less is known about ErbB4 participation in cardiac hypertrophy. We evaluated the role of cardiomyocyte ErbB4 in developmental-, exercise-, and angiotensin-induced hypertrophy. For adult studies, ErbB4 was deleted in αMHC-MerCreMer (cCre Tg+/−)/ErbB4 floxed (ErbB4ff) mice at ∼2 months of age with 10 injections of Tamoxifen (20 mg/kg/day). Mice were aged for up to 8 months, exposed to angiotensin II (1000 ng/kg/min, 14 days) or exercised (twice-daily swimming, 20 min/session increasing to 10 min/day to 90 min followed by 7 days at 90 min/session). Neonates (ErbB4ff or ErbB4ww) received temporal vein injections of AAV9-cTNT-eGFP-iCre (2.16 × 1011 viral particles) at p1 and were culled at p6. Three months after deletion of ErbB4 in adult hearts, contractile function was reduced in vivo (echocardiography, 16%) and ex vivo (isolated-perfused, 33%); however, deletion failed to modify heart size, survival for 8 months, or hypertrophy in response to angiotensin II or exercise. In neonates, the presence of iCre mRNA in hearts confirmed virus infection, and suppression of ErbB4 in ErbB4f/f mice was coincident with increased NRG1α, and reduced body and ventricular weights. Thus, ErbB4 is critical to cardiac hypertrophy and growth in neonatal mice, and maintains adult heart function (Figure 1).