Abstract 844: β IV -spectrin Regulates Cardiac Fibroblast Phenotype, Fibrosis, and Cardiac Function

• DOI: 10.1161/res.125.suppl_1.844
• Publication Date: 2019-10-16T17:53:59Z
• Authors: Nehal J Patel; Drew M Nassal; Benjamin W Scandling; Amara D Greer-Short; Sathya D Unudurthi; Xianyao Xu; Peter J Mohler; Keith J Gooch; Thomas J Hund
• Keywords: Cardiac Fibrosis

Increased fibrosis is associated with cardiac dysfunction and arrhythmias. Activation of quiescent fibroblasts (CFs) occurs in response to injury although the underlying mechanistic pathways remain unclear. The cytoskeletal protein β IV -spectrin has been shown control targeting activity multifunctional transcription factor Signal Transducer Activator Transcription 3 (STAT3) for maladaptive remodeling. mechanism linking spectrin altered STAT3 signaling, fibrosis, function remains unknown. objective this study was investigate role stress-induced disruption -spectrin/STAT3 complex modulating CF phenotype, function. Cardiac (echocardiography) (Masson’s trichrome) were evaluated adult wildtype (WT) qv 4J mice expressing truncated lacking interaction. A subset WT subjected 6 wks transaortic constriction (TAC) induce heart failure. From these groups, CFs isolated from ventricles analyzed localization, gene expression, activity. treated selective inhibitor S3I-201 (100μM) or transfected 72 hrs fragment repeat 10 C-terminus (β IV,10-C , contains binding motif). Ejection fraction decreased TAC relative baseline (49.5±0.85% vs 34.9±2.2% 63.2±0.60% respectively, p<0.05, N=5. Ventricular augmented compared (2.4±0.09% 3.2±0.25% 0.48±0.01% N=5). showed mislocalization (49.7±10.7% nuclear accumulation 5.3±.1.8% WT, N=5) higher transcriptional (2.6±0.17-fold increase over N=9). In parallel, displayed elevated expression fibrotic genes activation. At functional level, increased proliferation (1.9±0.19-fold at 24 hrs, N=4). inhibition S31-201 transfection normalized WT. These studies identify a requirement normal signaling phenotype CFs.