Abstract Body: Background: Cardiac fibrosis is driven not only by the magnitude of inflammatory signaling but by its temporal regulation. Recombinant GDF11 (rGDF11) reduces cardiac hypertrophy and interstitial fibrosis in pressure overload (TAC), AngII-induced stress, and aging models, where it can partially reverse established remodeling. However, the mechanisms by which GDF11 limits fibrosis remain undefined. Based on preliminary data demonstrating that rGDF11 reduces fibrosis between days 3–7 following AngII infusion, we hypothesized that GDF11 restrains cardiac fibrosis by accelerating resolution of NF-κB–mediated inflammation and suppressing sustained fibroblast activation.
Methods: Wild-type mice underwent AngII infusion (2mg/kg/day) with or without rGDF11 (1mg/kg). To define inflammatory kinetics (prevention paradigm), hearts were harvested daily from days 3 to 10 post-implantation. Macrophage states were characterized by flow cytometry, with parallel cytokine profiling and assessment of NF-κB pathway activity. To evaluate reversal of established fibrosis (reversion paradigm), rGDF11 was initiated after 14 days of AngII exposure.
Results: rGDF11 reduced ventricular fibrosis by day 7, localizing its protective effect to the inflammatory-to-fibrotic transition phase. Treatment accelerated the shift from pro-inflammatory to resolution-associated macrophage states and attenuated sustained NF-κB signaling. In established remodeling, rGDF11 reduced collagen deposition and suppressed persistent myofibroblast activation, consistent with fibroblast reprogramming rather than simple inhibition of matrix synthesis.
Conclusions: GDF11 restrains cardiac fibrosis by reshaping inflammatory timing and restoring fibroblast plasticity. These findings identify inflammatory resolution as a mechanistic node through which GDF11 governs immune–fibroblast communication and determines the trajectory of stress-induced remodeling, providing a framework for targeting fibrosis in cardiovascular disease.