Abstract 9531: Septin4 Deletion Prevents Hypertrophy to Heart Failure Transition After Transverse Aortic Constriction

Abstract

Introduction: In response to cardiac injury or increased workload, the mammalian heart undergoes ventricular remodeling to maintain cardiac function. Initially, these changes are compensatory, although ultimately, they lead to cardiomyocyte death and progression to heart failure. As one of the aspects of ventricular remodeling, cardiac fibrosis significantly reduces cardiac function. To identify potential new therapeutic targets, it is essential to understand the underlying mechanisms that regulate cardiac fibrosis. Previous research highlighted a possible interplay between TGF-β and Sept4. However, it is unknown if Sept4 is involved in TGF-β mediated cardiac fibrosis. Hypothesis: We hypothesized that Sept4 deletion prevents cardiac fibrosis and heart failure after transverse aortic constriction (TAC). Methods: 10-week old Sept4 knockout (S4KO) and wild type (WT) mice were subjected to TAC or Sham surgery. Cardiac function was assessed 1- and 4-week post-injury. At both timepoints, hearts were harvested and used for transcriptomic and proteomic analyses. For cell culture experiments, primary cells were isolated from healthy 10-week old S4KO and WT mice and treated with TGF-β (10 ng/ml) or vehicle. Results: S4KO mice demonstrated improved cardiac function compared to WT mice at 1- and 4-weeks after TAC. Importantly, both groups displayed comparable levels of cardiomyocyte contractility ex vivo , highlighting that the beneficial effects of Sept4 deletion is through the non-cardiomyocyte population. Moreover, S4KO hearts demonstrated decreased levels of fibrosis compared to WTs at baseline and after injury. Lastly, by using primary cardiac fibroblasts, we discovered that Sept4 deletion prevents fibroblast activation and collagen secretion primarily by inhibiting Smad2 phosphorylation. Conclusions: Our results identify Sept4 as a potent mediator of cardiac fibrosis through regulation of Smad2 activity.