Key result
ALOX5 knockdown attenuates aortic valve calcification by suppressing PLCG2/IP3 signaling.
Why the study?
The molecular mechanisms underlying calcific aortic valve disease (CAVD) progression remain unclear, necessitating identification of key metabolic genes involved in valve calcification.
Does ALOX5 knockdown or LTA4 treatment alter calcification and PLCG2/IP3 signaling in a human aortic valve interstitial cell model of calcific aortic valve disease?
Does ALOX5 knockdown or LTA4 treatment alter calcification and PLCG2/IP3 signaling in a human aortic valve interstitial cell model of calcific aortic valve disease?
ALOX5-mediated LTA4 production promotes calcification via the PLCG2/IP3 signaling pathway, identifying it as a potential novel therapeutic target for calcific aortic valve disease.
Background: Calcific aortic valve disease (CAVD) is a progressive disorder characterized by valve calcification; however, its underlying molecular mechanisms remain unclear. This study aimed to identify key metabolic genes involved in CAVD and investigate their roles in valve calcification. Methods: Transcriptome data from CAVD patients and controls were analyzed using bioinformatics and machine learning. Key genes were validated in clinical samples and a human aortic valve interstitial cell (HAVIC) calcification model. The effects of arachidonate 5-lipoxygenase (ALOX5) knockdown and leukotriene A4 (LTA4) treatment on calcification and phospholipase C gamma 2 (PLCG2)/inositol 1,4,5-trisphosphate (IP3) signaling were assessed using reverse transcription quantitative polymerase chain reaction, Western blot, Enzyme-Linked Immunosorbent Assay, and Alizarin Red S staining. Results: Bioinformatics analysis identified that ALOX5 and PLCG2, as key metabolic genes, were upregulated in the patients with CAVD. In clinical samples and calcified HAVICs, ALOX5 and PLCG2 expressions and their respective metabolites LTA4 and IP3 were significantly elevated. ALOX5 knockdown attenuated calcification and reduced PLCG2/IP3 signaling in HAVICs. Exogenous LTA4 treatment enhanced PLCG2 expression, IP3 production, and calcification in HAVICs, particularly under calcification-inducing conditions. These effects were mitigated by phospholipase C inhibition. Conclusions: This study revealed a novel mechanism for CAVD progression, where ALOX5-mediated LTA4 production enhanced PLCG2/IP3 signaling and exacerbated calcification in HAVICs. These findings suggest potential therapeutic targets for CAVD and provide new insights into the metabolic regulation of valve calcification.
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Liu et al. (2026) studied Calcific aortic valve disease (CAVD). ALOX5 knockdown and LTA4 treatment was evaluated on Calcification and PLCG2/IP3 signaling. ALOX5 knockdown attenuated calcification and reduced PLCG2/IP3 signaling in human aortic valve interstitial cells, while exogenous LTA4 treatment enhanced these effects.
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