Abstract 9582: Septin-4 Induces Cardiac Fibrosis After Pressure Overload

Abstract

Introduction: Under cardiac stress, the mammalian heart undergoes ventricular remodeling to maintain cardiac function. Although these remodeling changes are viewed as beneficial at first, they eventually lead to pathological fibrosis and apoptosis. The role of the small GTPase Septin-4 (Sept4) in regulating apoptosis and regeneration through survival of stem cells has been established in several organs. However, the role of Sept4 in the heart, an organ without stem cells, and a potential role in regulating the cardiac stress response is currently unknown. Hypothesis: Sept4 induces fibrosis and apoptosis in the mammalian heart after injury. Methods: 10-week-old Sept4 knockout (KO) and wild type (WT) mice underwent transverse aortic constriction injury (TAC). Functional and molecular analyses on KO and WT hearts were done either at baseline, 1- or 4-weeks post-injury timepoints depending on the assay. Results: Cardiac function was comparable between KO and WT mice under homeostatic conditions. After TAC injury, ejection fraction and fractional shortening were decreased significantly in WT mice but maintained in KO mice. The level of cardiomyocyte apoptosis was lower in KO hearts after injury with reduced development of fibrosis compared with WT hearts. We performed transcriptomic and proteomic analyses showing that KO hearts exhibited reduced levels of ECM deposition under both baseline and post-injury conditions. Furthermore, KO hearts were more compliant and demonstrated enhanced diastolic function compared to WT hearts. Mechanistically, Sept4 deletion blunted TGF-B signaling and Postn expression in cardiac fibroblasts after injury. In cultured cardiac fibroblasts, both Sept4 knockout and knockdown significantly decreased fibroblast activation after TGF-B treatment. Conclusions: We identified Sept4 as a crucial regulator of ECM remodeling in the heart. Sept4 deletion leads to reduced levels of cardiac fibrosis and alleviation of pressure overload-induced cardiac dysfunction. Overall, our study highlights Sept4 as a potential target to prevent pathological fibrosis in the heart.