Abstract 516: Endothelial Foxp1 Regulates Cardiac Remodeling via Tgfbeta and Et-1 Signal Pathway

Abstract

Rationale: Cardiac fibrosis and hypertrophy is common features in left ventricular remodeling that leads to heart failure. Forkhead box protein P-1 (Foxp1), a large modular transcriptional repressor that binds to DNA via the highly conserved forkhead DNA-binding domain, is crucial in coordinating the balance of cardiomyocyte proliferation and differentiation through cell lineage-specific regulation during cardiac development. However, its role in adult pathological cardiac remodel remains to be clarified. Objective: We seek to determine the role and the underlying mechanisms of Foxp1 in cardiac fibrosis and hypertrophy. Methods and Results: Foxp1 was highly expressed in endocardium and cardiac microvascular endothelial cells, significantly reduced following AngII stimulation. Loss of endothelial Foxp1 increased AngII-mediated cardiac fibrosis, which was accompanied by myofibroblast proliferation and endothelial-mesenchymal transition (endMT) with elevated expression of fibrotic matrix genes. TGF-β signal pathway was identified as Foxp1 direct downstream target gene in endothelial cells to regulate the fibrosis. Increased AngII-mediated cardiac hypertrophy was observed when loss of endothelial Foxp1, with elevated cardiac hypertrophic genes and fetal myosin gene (myh7) expression but reduced adult mature myosin gene (myh6) expression via endothelial ET-1 signal. The pathological remodel in endothelial Foxp1 deficient mutant mice finally led to worsen cardiac diastolic dysfunction as shown by elevated E/e’ ratio in echocardiogram. Moreover, the similar pathological remodel and worsen cardiac diastolic and systolic dysfunction as shown by reduction of LV fractional shortening (FS) and ejection fraction (EF) were observed in pressure overload transverse aortic constriction (TAC) model when loss of endothelial Foxp1. Conclusions: This study uncovered a previously unrecognized anti-fibrotic and anti-hypertrophic role of Foxp1 in pathological cardiac remodel, which is achieved through the regulation of endothelial TGF-β/ET-1 signals, implying the promising therapeutic targets in pathological cardiac remodeling diseases and heart failure.