Abstract P2024: Myofibroblast Ccn3 Contributes To Adverse Cardiac Outcomes Following Myocardial Infarction

Abstract

Myofibroblast function is critical for initial scar formation and prevention of catastrophic rupture following myocardial infarction, however, extended myofibroblast activity promotes pathological remodeling through exacerbated scar formation, myocyte uncoupling, and regulation of immune cells. Therefore, there exists a need to identify molecular mediators of myofibroblast activity to therapeutically target these pathways and regulate the fibrotic response following cardiac injury. It has been demonstrated the suppression of the transcription factors Yap and Wwtr1 dramatically reduces myofibroblast activity, but the mechanisms by which these Hippo pathway factors mediate pathological remodeling remain relatively unknown. Recently, we have characterized the secreted matrix protein Ccn3 as an element of pathological remodeling. Regulated in part by the Hippo pathway, fibroblast expression of Ccn3 increases shortly after infarction. Administration of recombinant human CCN3 dramatically promoted cardiopathology in adult mice following injury, resulting in exacerbated injuries, reduced cardiac function, and expression of the pro-fibrotic Tgfβ1 pathway. Treatment of cultured cardiac fibroblasts with CCN3 resulted in increased expression of the fibrotic factors such as Fn1, Serpine1, and Ccn2. Conversely, genetic knockout of Ccn3 specifically in myofibroblasts promoted improved cardiac function following infarction as compared to injured control mice. Thus, Ccn3 is an enticing target for therapeutic strategies to suppress pathological remodeling.