BACKGROUND
Pathological cardiac fibrosis and hypertrophy, the common features of left ventricular remodeling, often progress towards heart failure. Forkhead box transcription factor P1 (Foxp1) in endothelial cells (ECs) has been shown to play an important role in heart development, however, the effect of EC-Foxp1 on pathological cardiac remodeling has not been well clarified. This study aims to determine the role of EC-Foxp1 in pathological cardiac remodeling and the underlying mechanisms.
METHODS
Foxp1 EC-specific loss-of-function and gain-of-function mice were generated and angiotensin II (AngII) infusion or transverse aorta constriction (TAC) operation mouse model were used to study the cardiac remodeling mechanisms. Foxp1 downstream target gene TGF-β1 were confirmed by ChIP and luciferase assays. Finally, the effects of TGF-β1 blockade on EC-Foxp1-deletion mediated pro-fibrotic and pro-hypertrophic phenotypic changes were further confirmed by pharmacological inhibition, and more specifically by RGD-peptide magnetic nanoparticle target delivery of TGF-β1-siRNA to ECs.
RESULTS
Foxp1 expression is significantly downregulated in cardiac ECs during AngII-induced cardiac remodeling. EC-Foxp1 deletion results in severe cardiac remodeling, including more cardiac fibrosis with myofibroblast formation and extracellular matrix protein production, and decompensated cardiac hypertrophy, and further exacerbation of cardiac dysfunction upon AngII infusion or TAC operation. In contrast, EC-Foxp1 gain-of-function protects against pathological cardiac remodeling and improves cardiac dysfunction. TGF-β1 signals are identified as Foxp1 direct target genes and EC-Foxp1 deletion upregulates TGF-β1 signals to promote myofibroblast formation through fibroblast proliferation and transformation, resulting in severe cardiac fibrosis. Moreover, EC-Foxp1 deletion enhances TGF-β1-promoted endothelin-1 (ET-1) expression, which significantly increases cardiomyocyte size and reactivates cardiac fetal genes leading to pathological cardiac hypertrophy. Correspondingly, these EC-Foxp1-deletion mediated pro-fibrotic and pro-hypertrophic phenotypic changes and cardiac dysfunction are normalized by blockade of TGF-β1 signals through pharmacological inhibition and RGD-peptide magnetic nanoparticle target delivery of TGF-β1-siRNA to ECs.
CONCLUSIONS
EC-Foxp1 regulates the TGF-β1-ET-1 pathway to control pathological cardiac fibrosis and hypertrophy, resulting in cardiac dysfunction. Therefore, targeting the EC-Foxp1-TGF-β1-ET-1 pathway might provide a future novel therapy for heart failure.