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Histone lactylation enhances m6A-mediated PDK4 stabilization to drive osteogenic differentiation in calcific aortic valve disease

ABSTRACT: Calcific aortic valvular disease (CAVD) is characterized by progressive thickening and calcification of the valvular leaflets. Emerging evidence suggests that glycolysis, particularly regulated by pyruvate dehydrogenase kinase 4 (PDK4), plays a significant role in calcification-related diseases. Nevertheless, the mechanisms by which PDK4 affects glycolysis and influences CAVD remain unexplored. This study investigated the contribution of PDK4 to glycolytic reprogramming and osteogenic differentiation in CAVD. Osteogenic differentiation of human valvular interstitial cells (VICs) and CAVD valves was associated with enhanced glycolysis, leading to increased lactate production that further promoted VICs' calcification. PDK4 expression was significantly upregulated in both osteogenically differentiated VICs and CAVD valves. Silencing PDK4 reduced osteogenic differentiation in VICs, whereas PDK4 overexpression aggravated differentiation and increased glycolytic activity. Mechanistically, PDK4 facilitated nuclear translocation of Yes-associated protein (YAP), a key regulator of the Hippo signaling pathway, thereby enhancing RUNX2 transcription and promoting osteogenic differentiation. Nuclear accumulation of lactate increased H3K18 lactylation, which stabilized PDK4 mRNA through the METTL3-m6A-YTHDF1 pathway, establishing a positive feedback loop. This study identifies mechanisms by which glycolysis drives CAVD progression and highlights PDK4 as a potential molecular target for therapeutic intervention.

ORGANISM(S): Homo sapiens

PROVIDER: GSE309520 | GEO | 2026/05/01

REPOSITORIES: GEO

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Project description:Calcific aortic valve disease (CAVD) is increasingly affecting the aging population and is involved in the osteogenic reprogramming of valvular interstitial cells (VICs). However, the exact underlying molecular regulatory mechanisms remain unclear. Vesicle-associated membrane-protein-associated protein B (VAPB) mediates the generation of contact sites between the endoplasmic reticulum (ER) and other cellular membranes. However, the role of VAPB in CAVD remains unclear. This study was to elucidate the relationship between vesicle-associated membrane protein-associated protein B (VAPB) and aortic valve calcification at both tissue and cellular molecular levels, exploring potential regulatory mechanisms. The expression levels of VAPB were assessed using immunohistochemical analysis. Osteogenic differentiation and calcification levels of valve interstitial cells (VICs) were assessed through alizarin red staining, calcium content quantification, and the detection of the osteogenic marker RUNX2. Gene set enrichment analysis was used, and immunoprecipitation was performed. VAPB expression was significantly upregulated in the aortic valve leaflets of patients with calcific aortic valve disease (CAVD) compared to normal aortic valves. VICs with VAPB overexpression exhibited a significant increase in calcium content (p < 0.001) and upregulation of the transcription factor RUNX2 and the osteogenic markers osteocalcin and osteopontin at both mRNA and protein levels (p <0.01). Conversely, VAPB knockdown reduced osteogenic differentiation in VICs. Furthermore, VAPB overexpression led to the enhanced expression of p-SMAD1/5/9 through activation of the SMAD signaling pathway (p < 0.05), while inhibition of the SMAD pathway abrogated the pro-calcification effects of VAPB. Dual immunofluorescence staining demonstrated colocalization of VAPB with SMAD1/5/9, and immunoprecipitation confirmed an interaction between VAPB and SMAD1/5/9. The findings indicate that VAPB promotes osteogenic differentiation in aortic valve interstitial cells by activating the SMAD signaling pathway.

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Histone lactylation enhances m6A-mediated PDK4 stabilization to drive osteogenic differentiation in calcific aortic valve disease

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