Abstract 13: Hippo Signaling Deletion During Heart Failure Reverses Functional Decline
The heart has long been thought of as a static organ incapable of repair. Recent findings have challenged this view of the heart, and have demonstrated that mature cardiomyocytes are capable of re-entering the cell-cycle. However, there is still paucity in understanding endogenous mechanisms preventing cardiomyocyte self-renewal. Our approach is to apply developmental mechanisms of cardiomyocyte cell-cycle control to the damaged heart by altering the Hippo signaling pathway.
During development Hippo signaling regulates intrinsic organ size. The core mammalian Hippo pathway includes the Ste20-like serine/threonine kinases Mst1 and Mst2, homologous to the Drosophila Hippo kinase. A subsequent kinase cascade leads to the phosphorylation of the transcription factor Yap. Phosphorylated Yap is sequestered in the cytoplasm, thus preventing transcriptional activity. We previously demonstrated Hippo signaling controls cardiomyocyte proliferation during development to restrain heart size. Additionally, using both the Apex resection (AR) and LAD-ligation (MI) models of cardiac damage, in a Hippo signaling deletion mouse, we demonstrated cardiac regeneration. Indicated by preserved cardiac function and reduced fibrotic scar formation. Additionally, these hearts display cardiomyocyte proliferation as marked by EDU incorporation, pHH3, AurkB, and Ki67 staining.
We are taking a new approach to determine the effect of Hippo signaling deletion on the failing heart, by inducing Hippo deletion after fibrotic scar formation has already occurred. To Thus far our results indicate functional recovery of the failing heart only after inducible deletion of Hippo signaling. Consistent with our previous data, preliminary results indicate adult cardiomyocytes after Hippo deletion re-enter the cell cycle. By altering Hippo signaling during heart failure and subsequently inducing cardiomyocyte proliferation we have established recovery of cardiac function. These results will greatly advance strategies to induce cardiac repair.
Author Disclosures: J. Leach: None. T. Heallen: None. M. Zhang: None. Y. Morikawa: None. J. Martin: None.
- © 2015 by American Heart Association, Inc.