Role of βIV-spectrin in control of STAT3 signaling in cardiac fibroblasts

The fibroblast, a connective tissue cell, secretes or breaks down the extracellular matrix (ECM) via chemical signaling that alters gene expression. This function is necessary in cardiac fibroblasts to maintain the structure and function of the heart, but when an injury occurs and fibroblasts are active for remodeling, these changes may become maladaptive, leading to cardiac fibrosis and reduced cardiac function. Signal transducer and activator of transcription 3 (STAT3) is a transcription factor that regulates genes involved in cell proliferation, survival, and synthesis of ECM components in fibroblasts. Preliminary studies from our group identified a novel complex involving the cytoskeletal protein βIV-spectrin and STAT3, important for normal subcellular distribution and activity of STAT3 in the heart. Loss of βIV-spectrin function promotes STAT3 mislocalization, changes in gene expression, and maladaptive cardiac remodeling with relevance to animal models of heart failure and human patients. While previous work has utilized a cardiomyocyte specific βIV-spectrin knockout mouse to examine the role of spectrin/STAT3 complex in cardiomyocytes, the question remains whether this complex plays a broader role in non-myocytes (e.g. fibroblasts). Furthermore, questions remain about the mechanism by which STAT3 mislocalization results in altered gene transcription in any cell (myocyte or otherwise). The overall goal of this study is to better understand the relationship between changes in βIV-spectrin function and altered gene transcription in the heart. This study tests the hypothesis that βIV-spectrin associates with STAT3 in cardiac fibroblasts to directly regulate gene expression of proteins related to stress signaling and cardiac remodeling. The following mouse models were used for this study: wild type and qv4J (lacks spectrin/STAT3 interaction). First, confocal microscopy was used to study the distribution of STAT3 in fibroblasts in the presence and absence of spectrin/STAT3 interaction. Next, echocardiography was used to assess cardiac function and heart sections were analyzed for fibrosis. Finally, quantitative PCR (qPCR) was used to quantify the expression of important STAT3 regulated genes in the fibroblasts. Results show STAT3 localization to the nucleus, decreased ejection fraction, increase in left ventricular (LV) chamber diameter, LV wall thinning, increased fibrosis, and increased mRNA expression of COL14a in the qv4J mouse model compared to wild type. The mechanisms seen in cardiomyocytes and fibroblasts are potential targets for reducing or inhibiting remodeling effects. NIHAmerican Heart AssociationSaving Tiny Hearts SocietyJames S. McDonnell FoundationOSU Office of Undergraduate ResearchA one-year embargo was granted for this item.Academic Major: Biomedical Engineerin