Cardiomyocyte FGFR1 Signaling Attenuates Adverse Ventricular Remodeling and Preserves Cardiac Function

Background: Heart failure (HF) is characterized by progressive adverse remodeling. However, the underlying molecular mechanisms governing the progression of pathological remodeling and ventricular dysfunction remain incompletely defined. Fibroblast growth factor receptor 1 (FGFR1) regulates growth factor signaling in the heart, yet its role in HF is limited. Methods: Proteomic and transcriptomic analyses were performed on left ventricular tissue from patients with HF to identify dysregulated remodeling pathways. FGFR1 expression and protein kinase B (AKT) signaling were examined in human hearts, in mice subjected to chronic isoprenaline infusion, and in cardiomyocyte-specific FGFR1 knockout (FGFR1cKO) mice. In vitro studies were conducted in neonatal rat cardiomyocytes (NRCMs) and rat myoblasts (H9C2) using siRNA-mediated FGFR1 knockdown and stimulating AKT phosphorylation by the specific activator SC-79 under isoprenaline-induced β-adrenergic stress. Genetic restoration of FGFR1 was achieved using adeno-associated viral subtype 9 (AAV9) delivery of FGFR1 after the onset of remodeling, followed by echocardiographic, histological, and molecular analyses. Results: Human HF hearts exhibited broad dysregulation of remodeling pathways. Notably, AKT signaling was markedly suppressed. Reduced FGFR1 expression was accompanied by decreased AKT phosphorylation in human HF hearts. Consistently, chronic isoprenaline stress reduced cardiac FGFR1 expression in vivo and in vitro. Cardiomyocyte-specific FGFR1 deletion exacerbated systolic dysfunction and promoted ventricular dilation. Mechanistically, FGFR1 deficiency suppressed AKT activation, which contributed to cardiac pathological remodeling upon isoprenaline stress. In cardiomyocytes with FGFR1 knockdown, cardiomyocyte injury and maladaptive transcriptional responses were amplified under β-adrenergic stress. Of note, these detrimental effects were rescued by pharmacological activation of AKT using its activator, SC-79. Therapeutically, genetic FGFR1 re-establishment attenuated cardiac pathological remodeling and restored systolic function under longer-term isoprenaline stress, at least partially through maintenance of AKT activation. Conclusions: The current study has demonstrated that cardiac FGFR1 signaling exhibits cardioprotective potential that mitigates adverse ventricular remodeling and rescues cardiac function under pathological stress. Therefore, targeting FGFR1 signaling represents a potential strategy to prevent pathological remodeling and HF.