Menaquinone-4 Accelerates Calcification of Human Aortic Valve Interstitial Cells in High-Phosphate Medium through PXR
| Autor: | Mari Chiyoya, Tadaatsu Imaizumi, Kazuhiko Seya, Ken-Ichi Furukawa, Xu Liu, Zaiqiang Yu, Wei Yang, Kazuyuki Daitoku, Ikuo Fukuda, Shigeru Motomura, Motonori Tsuji |
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| Rok vydání: | 2019 |
| Předmět: |
0301 basic medicine
Aortic valve medicine.medical_specialty medicine.medical_treatment Phosphatase Cell Culture Techniques Bone Morphogenetic Protein 2 Gene Expression Phosphates 03 medical and health sciences 0302 clinical medicine Valve replacement Internal medicine medicine Humans Cells Cultured Pharmacology Dose-Response Relationship Drug Chemistry Vitamin K2 Pregnane X Receptor Calcinosis Vitamin K 2 Aortic Valve Stenosis medicine.disease Alkaline Phosphatase Culture Media 030104 developmental biology Endocrinology medicine.anatomical_structure Aortic valve stenosis Aortic Valve Molecular Medicine Alkaline phosphatase Warfarin Aortic valve calcification 030217 neurology & neurosurgery Calcification Signal Transduction |
| Zdroj: | The Journal of pharmacology and experimental therapeutics. 372(3) |
| ISSN: | 1521-0103 |
| Popis: | Recently, we confirmed that in human aortic valve interstitial cells (HAVICs) isolated from patients with aortic valve stenosis (AVS), calcification is induced in high inorganic phosphate (high-Pi) medium by warfarin (WFN). Because WFN is known as a vitamin K antagonist, reducing the formation of blood clots by vitamin K cycle, we hypothesized that vitamin K regulates WFN-induced HAVIC calcification. Here, we sought to determine whether WFN-induced HAVIC calcification in high-Pi medium is inhibited by menaquinone-4 (MK-4), the most common form of vitamin K2 in animals. HAVICs obtained from patients with AVS were cultured in α-modified Eagle's medium containing 10% FBS, and when the cells reached 80%-90% confluency, they were further cultured in the presence or absence of MK-4 and WFN for 7 days in high-Pi medium (3.2 mM Pi). Intriguingly, in high-Pi medium, MK-4 dose-dependently accelerated WFN-induced HAVIC calcification and also accelerated the calcification when used alone (at 10 nM). Furthermore, MK-4 enhanced alkaline phosphatase (ALP) activity in HAVICs, and 7 days of MK-4 treatment markedly upregulated the gene expression of the calcification marker bone morphogenetic protein 2 (BMP2). Notably, MK-4-induced calcification was potently suppressed by two pregnane X receptor (PXR) inhibitors, ketoconazole and coumestrol; conversely, PXR activity was weakly increased, but in a statistically significant and dose-dependent manner, by MK-4. Lastly, in physiologic-Pi medium, MK-4 increased BMP2 gene expression and accelerated excess BMP2 (30 ng/ml)-induced HAVIC calcification. These results suggest that MK-4, namely vitamin K2, accelerates calcification of HAVICs from patients with AVS like WFN via PXR-BMP2-ALP pathway. SIGNIFICANCE STATEMENT: For aortic valve stenosis (AVS) induced by irreversible valve calcification, the most effective treatment is surgical aortic or transcatheter aortic valve replacement, but ∼20% of patients are deemed unsuitable because of its invasiveness. For effective drug treatment strategies for AVS, the mechanisms underlying aortic valve calcification must be elucidated. Here, we show that menaquinone-4 accelerates warfarin-induced calcification of AVS-patient human aortic valve interstitial cells in high inorganic phosphate medium; this effect is mediated by pregnane X receptor-bone morphogenetic protein 2-alkaline phosphatase signaling, which could be targeted for novel drug development. |
| Databáze: | OpenAIRE |
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