Endothelin-1 inhibits cardiomyocyte proliferation and heart regeneration

About This Grant

ABSTRACT The goal of our research program is to regenerate human hearts. We define heart regeneration as the replacement of a numerical deficit of cardiomyocytes through proliferation. This definition includes heart regeneration to replace the cardiomyocyte loss from a myocardial infarction, as well as replacing the cardiomyocyte proliferation defects in congenital heart disease, the most common birth defect. In contrast to adults, young mammals, especially neonates, have active cardiomyocyte proliferation. This points to the incredible potential for regeneration in infants. Consequently, we have directed our research to investigate the mechanisms of cardiomyocyte proliferation in neonatal mice, with the long-term goal of directing heart regeneration in pediatric patients with congenital heart disease and in adult patients after myocardial infarction. This application is for the characterization of a cardiomyocyte proliferation inhibitor, the extracellular factor, endothelin-1 (ET-1), and its receptor (ET-RA), a G protein-coupled receptor (GPCR). Although extracellular factors that stimulate cardiomyocyte proliferation have been defined, a well-characterized one being neuregulin1 (NRG1), which we have identified (Bersell et al., Cell 2009 and Polizzotti et al., Sci Translat Med 2015), the concept of inhibitors is novel. The concept of extracellular inhibition of cardiomyocyte proliferation is significant because inhibitors could dominate over pro-proliferative factors and render their administration ineffective. This is important for potential clinical application of stimulators, for example, recombinant neuregulin, and other factors, to direct cardiomyocyte proliferation in patients. The translation into the clinic may occur in the near future since administration of recombinant neuregulin is currently in clinical trials. Consequently, knowledge of the mechanisms by which inhibitors act is critical for clinical translation. Endothelin-1 receptor blockers (ET-RA), such as Ambrisentan, are in the clinic, indicating a path for translation. We propose to test the central hypothesis that endothelin-1 and its receptor, ET-RA, constitute a mechanism, whose inhibitory effect on cardiomyocyte proliferation is activated by heart injury or disease. Our preliminary results show that endothelin-1, by activating ET-RA, reduces M-phase and cytokinesis activity. These results position ET-RA as a compelling molecular target to direct cardiomyocyte proliferation. We will test the hypothesis using genetic and surgical mouse models and in induced pluripotent stem cell (hiPSC)-derived cardiomyocytes from human patients with congenital heart disease. We will take an innovative research approach that has been validated by prior work of the investigators. This proposal combines the synergistic skills of the co-I, Dr. Honghai Liu, with whom the PI has a history of very impactful collaborations, and the co-I, Dr. Todd Evans, who will extend strengths with hiPSC. The necessary reagents are in place, and the environment is exceptional to accomplish this research at Weill Cornell Medical.