Abstract Body: Background: Excessive fibrosis and chronic inflammation are key contributors to adverse cardiac remodeling and dysfunction following myocardial infarction (MI). The interaction between fibroblasts, which drive fibrosis, and immune cells, which regulate inflammation, is essential for heart repair and remodeling. However, the molecular mechanisms underlying the communication between fibroblasts and immune cells remain poorly understood. The NFκB pathway is central to the inflammatory response and fibroblast activation, but its role in cardiac ischemic injury and remodeling is unknown.
Methods and Results: NFκB was deleted from or inserted into fibroblasts with tamoxifen-inducible Tcf 21-promoter-driven Cre recombinase. Mice were given a tamoxifen diet for four weeks, followed by a one-week washout period, before undergoing MI surgery. Echocardiography was performed at baseline, two, and four weeks post-MI. Hearts were harvested at four weeks for qRT-PCR and flow cytometry analysis. NFκB deletion restricted MI-induced cardiac dysfunction, as evident from restored ejection fraction (EF) and fractional shortening (FS). The protective phenotype of NFκB deletion was further evident from the decreased expression of cardiac damage markers ANP and BNP. Hyperactivation of fibroblasts and excessive inflammation are established to be detrimental to heart function. Interestingly, NFκB deletion reduced the activation of fibroblasts by reducing its conversion into myofibroblasts. Further, NFκB deletion reduced macrophages, neutrophils, and T lymphocytes recruitment in the heart, indicating a protective phenotype of NFκB deletion. In parallel, Knock in studies validated the role of fibroblast-specific NFκB in fibroblast activation, excessive inflammation, and dysfunction. These studies also found the role of fibroblast-NFκB in the activation of the profibrotic TGF-β1/SMAD-3 pathway.
Conclusion: These findings suggest that fibroblast-specific NFκB plays a critical role in fibroblast activation, inflammation, and dysfunction after MI. This study highlights NFκB as a potential therapeutic target for mitigating cardiac pathogenesis.