メナキノン-4は高リン酸条件下でヒト石灰化大動脈弁から得た間質細胞の石灰化を促進する

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  • Menaquinone-4 accelerates calcification of human aortic valve interstitial cells in high-phosphate medium through PXR

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<p>Recently, we confirmed that menaquinone-4 (MK-4), the most common form of vitamin K2 in animals, induced the calcification of human aortic valve interstitial cells (HAVICs) isolated from aortic valve stenosis (AVS) patients in high inorganic phosphate (high-Pi) medium via BMP2-ALP pathway. However, the mechanism of MK-4-induced BMP2 expression is unclear. There is a report that MK-4 can enhance collagen accumulation through pregnane X receptor (PXR) resulting in bone formation. So, the involvement of PXR in MK-4-induced calcification of HAVICs and BMP2 gene expression was investigated. HAVICs from AVS patients were cultured in α-MEM containing 10% FBS, and when the cells reached 80% confluence, they were further cultured in the presence or absence of MK-4 for 7 days in high-Pi medium (3.2 mM Pi). MK-4 dose-dependently accelerated PXR activity (EC50 6.2 nM). MK-4-induced calcification was potently suppressed by two PXR inhibitors, ketoconazole and coumestrol. In physiological-Pi medium, MK-4 alone also increased BMP2 gene expression, which was significantly suppressed by coumestrol. These results suggested that MK-4 accelerates the calcification of HAVICs from AVS patients through the PXR-BMP2-ALP pathway.</p>

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