Abstract 15113: C-cbl E3 Ubiquitin Ligase Regulates Cardiomyocyte Proliferation and Cardiac Regeneration

Abstract

Background: Neonatal mammalian hearts display considerable regenerative capacity following injury through cardiomyocyte proliferation. However, this regenerative capacity is lost by post-natal day 7. Previous studies have shown the role of receptor tyrosine kinases (RTKs) on cardiomyocyte proliferation and cardiac regeneration. However, the mechanisms that control RTK turnover and signaling during and beyond the regenerative window of the heart remain largely unknown. Hypothesis: This study investigates the role of the proto-oncogene Casitas b-lineage lymphoma (c-Cbl), an adaptor protein with an intrinsic E3 ubiquitin ligase activity that targets RTKs, on cardiomyocyte proliferation and cardiac regeneration following myocardial infarction (MI). Methods and Results: c-Cbl expression was downregulated during post-natal development and re-expressed in the adult heart following MI. RNA-sequencing studies reveal a distinct transcriptional profile in c-Cbl-deficient mouse hearts, of which c-Cbl deletion substantially delayed cardiomyocyte maturation and enhanced cardiomyocyte proliferation. c-Cbl deletion also extended the regenerative window for post-natal mouse hearts following MI and enhanced the ability to recover following MI with improved myocardial function, reduced scar formation, and increased cardiomyocyte cell-cycle activity. Mechanistically, c-Cbl E3 ubiquitin ligase activity was markedly enhanced in the adult than neonatal heart following MI, along with increased ubiquitination and downregulation of key RTKs involved in cardiomyocyte proliferation. Intriguingly, adenoviral expression of a c-Cbl mutant deficient in E3 ligase enhanced RTK signaling and promoted cardiomyocyte proliferation in vitro. Conclusions: These results reveal c-Cbl as a critical regulator of cardiomyocyte proliferation and a potential therapeutic target for the maintenance of cardiac regeneration and function following MI.