Abstract 17425: Matricellular Protein CCN1 Modulates Post-Infarct Scar Integrity and Structure

Abstract

Introduction: Collagen deposition is required for repair of the heart following myocardial infarction (MI). As collagen abundance increases, so does its alignment, potentially influencing scar integrity. Because cell-matrix interactions regulate fibroblast behavior and matrix dynamics, adhesive factors, like cellular communication network (CCN) proteins, may contribute to post-MI scar formation. CCN1's role in skin collagen modulation and its recent emergence as a heart failure biomarker indicate its potential contribution to post-MI matrix remodeling. Consequently, we focused on CCN1 as a potential regulator of collagen organization. Hypothesis: CCN1 guides collagen alignment to support scar integrity via enhancing fibroblast-matrix interactions. Methods & Results: Tamoxifen (TAM)-inducible Ccn1 fibroblast-specific KO ( Ccn1 -/- ) and control ( Ccn1 fl/fl ) mice (16-20 wk old) received TAM 3 wk prior to permanent coronary artery ligation. Cardiac function, heart mass, and scar structure were evaluated 1 wk post-MI using echocardiography, gravimetrics, and imaging techniques (picrosirius red, second harmonic generation, and transmission electron microscopy). Ccn1 -/- mice exhibited decreased survival (A) and an increased incidence of cardiac rupture compared to Ccn1 fl/fl (B-C). There were no differences in cardiac function or scar size among the groups. Macro- (E-F) and micro- (G) level structural analyses uncovered significant reductions in collagen organization in Ccn1 -/- mice. RNAi-mediated CCN1 depletion in fibroblasts resulted in reduced focal adhesion (FA) formation in culture (43.0 FA/cell ± 5.6 vs. 89.3 FA/cell ± 9.6; Mean ± SEM, p=0.0013, n=7), highlighting its role in facilitating fibroblast-ECM interactions. Conclusions: CCN1 is required for post-MI scar integrity. CCN1 may regulate fibroblast-ECM interactions to alter collagen organization.