EP300/CREBBP induces osteogenic differentiation of valve interstitial cells by promoting the SPP1 expression in calcific aortic valve disease

Secreted phosphoprotein 1 (SPP1) has been identified as a driver of fibrosis and inflammation, while its contribution to calcific aortic valve disease (CAVD) has not been clarified. In this research, we explored the possible role of SPP1 and the underlying molecular mechanism in CAVD. C57BL/6J mice were subjected to a high-fat diet (HFD), and human valve interstitial cells (VICs) were induced with the osteogenic medium (OM) for modeling. SPP1 was highly expressed in the human calcific aortic valve and VICs induced with OM, and its transcription was regulated by EP300/CREBBP. Knockdown of SPP1 inhibited the osteogenic differentiation of VICs, and overexpression of SPP1 reversed the repressive effect of EP300/CREBBP inhibitor on the osteogenic differentiation of VICs. EP300/CREBBP inhibitor ameliorated the aortic valve thickening and calcification in mice induced with HFD, and combined overexpression of SPP1 reversed the effect. In conclusion, the present findings suggest that EP300/CREBBP is dependent on SPP1 to induce osteogenic differentiation of VICs, thereby promoting the development of CAVD.

Calcific aortic valve disease; EP300/CREBBP; Osteogenic differentiation; SPP1; Valve interstitial cells.