Window of opportunity for developing effective medical intervention for calcific aortic valve disease

Graphical AbstractscRNA-seq analysis of human aortic valve samples from young, elderly, and calcified CAVD patients reveals the pseudo-time differentiation trajectory of VICs transdifferentiating to osteogenic-like cells. Ageing, haemodynamic stress, reactive oxygen species, and inflammation, followed by lipid accumulation, trigger procalcific LUM expression in CD44high VICs which induces VIC osteogenesis via activation of inflammatory pathways and augmentation of cellular glycolysis, resulting in the accumulation of lactate. In addition to regulating the inflammatory response, LUM promotes the expression of the osteogenic genes (ALP, Runx2, and BMP2), enhancing the aortic valve calcification process in CAVD through epigenetic modifications—lactylation of the H3 histone in lysine residues 14 and 9. ALP, alkaline phosphatase; BMP, bone morphogenetic protein; CAVD, calcific aortic valve disease; LUM, lumican; Runx2, Runt-related transcription factor 2; scRNA-seq, single-cell RNA sequencing; VIC, valve interstitial cellOpen in new tabDownload slide