Abstract P1082: The Role Of Shroom3 Protein In Cardiac Regeneration And Repair

Abstract

The cardiac injury response mainly depends on species and developmental stage. In a pro-regenerative context, including zebrafish and neonatal mice, following cardiac injury and death of cardiomyocytes (CMs), remaining CMs re-establish a functional cytoarchitecture, proliferate, and integrate into a re-muscularized heart. However, in a non-regenerative context, existing CMs do not readily proliferate, but instead, remodel their cytoarchitecture and undergo hypertrophy. Of note, CM cytoskeletal structure and intercalated disc (ICD) play a key role in regulating cell signaling and cardiac function. In zebrafish, Shroom3 (Shrm3) is a protein that mediates CM morphology, proliferation, and ICD integrity. Previous studies suggest that Shrm3 deletion results in increased CM proliferation in embryonic mice and zebrafish. Here, we investigate the function of Shrm3 on CM and its role in mediating a regenerative response to myocardial injury. To date, the role of Shrm3 in regulating the postnatal CM cell cycle has not been explicitly explored due to high lethality in global Shrm3 knockout mouse models. Thus, we developed a tamoxifen-inducible CM-specific Shrm3 deletion mouse model (Shrm3 fl/fl ;Myh6 MCM ) to study the Shrm3 role in both neonate and adult mice. At P7, Shrm3 fl/fl ;Myh6 MCM uninjured mice showed increased EdU incorporation in CM nuclei compared to wildtype controls suggesting that as in zebrafish and embryonic mice, Shrm3 knockout increased CM cell cycle activity postnatally. We performed apical resection injury on P1 mice and at 21 days post-injury (dpi) Shrm3 fl/fl ;Myh6 MCM CMs displayed compromised ICDs. Trichrome staining of 21 dpi hearts revealed minimal scar formation in Shrm3 fl/fl ;Myh6 MCM mice, however, we observed aberrant regeneration of the ventricular apex as indicated by invagination of the cardiac apex and significantly reduced ejection fraction at 21 dpi. Thus, our data suggest that Shrm3 deletion in postnatal CMs remodels cell junctions and increases CM cell cycle activity. Our future studies will address the Shrm3 function(s) in cardiac regeneration and repair in injured adult mice to develop potential therapeutic strategies.