Severe forms of coronary artery disease lead to heart attacks in more than a million Americans each year, causing irreversible damage to their heart muscle.  Current therapies prolong survival by protecting remaining cardiomyocytes, but they are unable to overcome the fundamental problem of replacing lost cardiomyocytes.  Although the neonatal mammalian heart is capable of substantial regeneration following injury, this regenerative capacity largely disappears in the first week after birth.  Thus, understanding which molecular pathways govern cardiomyocyte proliferation is a high priority in the effort to explore new treatments for heart failure post myocardial infarction (MI).

Shortly after birth, muscle cells of the mammalian heart lose their ability to divide.  At the same time, the N-cadherin/catenin cell adhesion complex accumulates at the cell termini, creating a specialized type of cell-cell contact called the intercalated disc (ID).  The ID serves as an organizing center for various cell surface proteins including junctional complexes critical for cell-cell attachment and cell-cell communication.  To investigate the role of cadherin/catenin-mediated adhesion and signaling in the development of the ID and its function of the adult heart, we use transgenic loss-of-function and gain-of-function mouse models. Cardiac-restricted knockout of N-cadherin demonstrated for the first time the importance of cadherin-mediated adhesion in maintaining normal electrical conduction in the heart.  More recently, our laboratory demonstrated that simultaneous depletion of both aE- and aT-catenin, referred as a-catenin double knockout (DKO), resulted in perturbation of ID formation and sustained cardiomyocyte proliferation beyond the first week of life.  The increased proliferation in the a-catenin DKO mice requires the Yes-associated protein (Yap), a transcriptional coactivator that binds to the TEAD transcriptional factors to induce expression of cell cycle regulators and other target genes.  We hypothesize that, after a heart attack, the surviving cardiomyocytes have altered cell-to-cell connections that can be manipulated in order to promote cardiomyocyte de-differentiation and proliferation.  In support of this idea, the Radice lab found that manipulating the adhesion complex in a mouse MI model led to increase cardiomyocyte proliferation and improvement in heart pumping function. Using various mouse models, we continue to investigate the relationship between cardiac mechanics, function, and growth in the normal and diseased heart.

American Heart Association