Thrombospondin-1 Silencing Ameliorates Osteoblastic Differentiation of Aortic Valve Interstitial Cells via Inhibiting Nuclear Factor-κB Pathway

Abstract

Objective: Calcific aortic valve disease (CAVD) is a progressive cardiovascular condition driven by the osteogenic differentiation of valve interstitial cells (VICs), with no effective drug therapies currently available. Hence, our objective is to investigate the impact of thrombospondin-1 (TSP-1) silencing on CAVD progression.

Methods: In vitro experiments were employed using human primary VICs with TSP-1 knockdown, cultured in osteogenic induction medium, and followed by analyses including western blot, alkaline phosphatase staining, alizarin red staining, immunofluorescence, and flow cytometry. In vivo experiments used two murine models of CAVD to determine the role of TSP-1 silencing on aortic valve calcification.

Results: We observed that silencing of TSP-1 reduced the osteogenic differentiation of VICs. Subsequent experiments demonstrated that TSP-1 knockdown suppressed nuclear factor-κB (NF-κB)–mediated inflammation during osteoblastic differentiation of VICs. Consistent findings were also observed in two murine models of CAVD.

Conclusions: The present study has shown that TSP-1 silencing could mitigate the development of CAVD by inhibiting NF-κB-mediated inflammation. We propose that targeting TSP-1-mediated NF-κB pathway could provide a potential therapeutic method for treating CAVD.