期刊
FRONTIERS IN CARDIOVASCULAR MEDICINE
卷 9, 期 -, 页码 -出版社
FRONTIERS MEDIA SA
DOI: 10.3389/fcvm.2022.885293
关键词
melatonin; osteogenesis; NF-kappa B; calcific aortic valve disease; cyclic AMP response element-binding protein; runt-related transcription factor 2; valvular interstitial cell
资金
- Wan Fang Hospital [107TMU-WFH-01-1, 108TMU-WFH-01-3]
- Taipei Medical University [TMU109-AE1-B09]
- Ministry of Science and Technology (Taiwan) [MOST108-2314-B-038-120]
This study determined the role of melatonin/MT1/MT2 signaling in valvular interstitial cell calcification and found that melatonin significantly reduced VIC calcification by targeting the NF-kappa B/CREB/Runx2 pathway, suggesting a potential therapeutic strategy for CAVD.
Calcific aortic valve disease (CAVD) is linked to high mortality. Melatonin inhibits nuclear factor-kappa B (NF-kappa B)/cyclic AMP response element-binding protein (CREB), contributing to CAVD progression. This study determined the role of melatonin/MT1/MT2 signaling in valvular interstitial cell (VIC) calcification. Western blotting and Alizarin red staining were used to analyze NF-kappa B/CREB/runt-related transcription factor 2 (Runx2) signaling in porcine VICs treated with an osteogenic (OST) medium without (control) or with melatonin for 5 days. Chromatin immunoprecipitation (ChIP) assay was used to analyze NE-kappa B's transcription regulation of NE-kappa B on the Runx2 promoter. OST medium-treated VICs exhibited a greater expression of NF-kappa B, CREB, and Runx2 than control VICs. Melatonin treatment downregulated the effects of the OST medium and reduced VIC calcification. The MT1/MT2 antagonist (Luzindole) and MT1 receptor neutralized antibody blocked the anticalcification effect of melatonin, but an MT2-specific inhibitor (4-P-PDOT) did not. Besides, the NF-kappa B inhibitor (SC75741) reduced OST medium-induced VIC calcification to a similar extent to melatonin at 10 nmol/L. The ChIP assay demonstrated that melatonin attenuated OST media increased NE-kappa B binding activity to the promoter region of Runx2. Activation of the melatonin/MT1-axis significantly reduced VIC calcification by targeting the NF-kappa B/CREB/Runx2 pathway. Targeting melatonin/MT1 signaling may be a potential therapeutic strategy for CAVD.
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