Endothelial Foxp1 overexpression inhibits endothelial-to-mesenchymal transition via suppressing Notch pathway activation to attenuate valvular calcification in chronic kidney disease

Forkhead box P1 (Foxp1) plays a key role in endothelial preservation and the suppression of inflammatory responses. However, its exact function in valvular calcification (VC) of chronic kidney disease (CKD) remains unclear. Our previous work showed that parathyroid hormone (PTH) contributes to CKD-related VC by driving valvular endothelial-to-mesenchymal transition (EndMT). Whether Foxp1 inhibits PTH-induced EndMT remains determined. This study investigates whether Foxp1 reduces VC by restraining EndMT and delineates the underlying mechanisms. The Foxp1-KI mice were crossed with the Cdh5-Cre (ERT2) mice to generate endothelial-specific Foxp1 knock-in mice (named Foxp1EC-OE). Here, it was found that Foxp1EC-OE mice exhibited reduced valvular calcification compared with CKD mice. Foxp1 overexpression suppressed valvular EndMT and inhibited Notch signaling by binding the Jagged-1 promoter and repressing its transcription. This led to decreased TGF-β1 secretion, thereby attenuating osteogenic transition of valvular interstitial cells. Additionally, Foxp1 restored endothelial integrity and reduced high mobility group box 1 protein (HMGB1)-driven macrophage infiltration. These findings identify Foxp1 as a key regulator of VC via Notch-mediated EndMT inhibition, revealing regulatory nodes in the Jagged-1/Notch pathway that may be amenable to future pharmacological targeting for CKD-related VC.