Abstract P1090: Inhibition of Inositol 1,4,5-trisphosphate receptors (ITP3Rs) in Cardiac Myofibroblasts Attenuates Post-Ischemic Cardiac Fibrosis

Introduction: Cardiac fibrosis is one of the major pathophysiologic features of ischemic cardiac disorders and substantial evidence has shown that cardiac fibroblasts and their activated form (myofibroblasts) are key players in heart failure progression. Inositol 1,4,5-trisphosphate receptors (ITP3Rs a.k.a. IP3Rs) are intracellular calcium release channels that play a critical role in calcium signaling, influencing cardiac remodeling and fibrosis. In both human and mouse fibroblasts, all three isoforms of ITP3Rs (ITP3R1, ITP3R2, and ITP3R3) are expressed, exhibiting redundant features. There is a lack of functional studies investigating the precise role of ITP3Rs in post-ischemic cardiac fibrosis in vivo . We assessed the hypothesis that after ischemia/reperfusion (I/R), ITP3Rs mediate the activation of cardiac fibroblasts and their persistence. Our data indicates that all three isoforms of ITP3Rs are increased in cardiac fibroblasts after myocardial infarction. Methods: Using a Cre/lox recombination strategy, we developed a novel mouse model (ITP3RKO) in which all isoforms of ITP3R are specifically deleted in cardiac myofibroblasts. This ITP3RKO model offers a unique opportunity to dissect the specific contributions of ITP3R to the progression of cardiac fibrosis, providing insights that were previously obscured by the compensatory mechanisms observed in models targeting individual isoforms. By selectively deleting all ITP3R isoforms in cardiac myofibroblasts, we can more accurately assess the role of ITP3R signaling in fibrosis, inflammation, and cardiac remodeling post-ischemia. This approach lays the foundation for more precise therapeutic strategies aimed at modulating ITP3R function in the context of heart disease. Results: Our data show that ITP3RKO mice exhibit reduced fibrosis and attenuated myocardial dysfunction compared to ITP3Rflox littermates after I/R. We further assessed the functional relationships between ITP3Rs and cardiac fibrosis in primary isolated fibroblasts at different time points and in response to established stimuli, to assess their survival, proliferative, migratory, and contractile capacity. Conclusion: Our studies are highly significant and innovative as they identify potential innovative therapeutic strategies to target excessive post-ischemic cardiac fibrosis and provide the first assessment of the role of ITP3R in activated myofibroblasts using a specific Cre/lox recombination model.