Menaquinone-4 Accelerates Calcification of Human Aortic Valve Interstitial Cells in High-Phosphate Medium through PXR

Yang, Wei; Yu, Zaiqiang; Chiyoya, Mari; Liu, Xu; Daitoku, Kazuyuki; Motomura, Shigeru; Imaizumi, Tadaatsu; Fukuda, Ikuo; Furukawa, Ken‐Ichi; Tsuji, Motonori; Seya, Kazuhiko

doi:10.1124/jpet.119.263160

Cited by 11 publications

(12 citation statements)

References 39 publications

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“…Similarly, MK7 had no effect on aortic calcification in haemodialytic chronic kidney disease patients or in uremic Sprague-Dawley rats 14,15 . Furthermore, MK-4 was reported to accelerate aortic valve calcification in cultured human aortic valve interstitial cells 16 . www.nature.com/scientificreports/…”

Section: Discussionmentioning

confidence: 99%

Menaquinone 4 increases plasma lipid levels in hypercholesterolemic mice

Weisell

Ruotsalainen

Näpänkangas

et al. 2021

Sci Rep

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In calcific aortic valve disease (CAVD) progressive valvular calcification causes aortic valve dysfunction. CAVD has several risk factors such as age and dyslipidemia. Vitamin K was shown to inhibit vascular calcification in mice and valvular calcification in patients with CAVD. We studied the effect of menaquinone 4 (MK4/vitamin K2) on valvular calcification in the hypercholesterolemic mouse model of CAVD. LDLr−/−ApoB100/100 male mice were fed with a Western diet for 5 months, with (n = 10) or without (n = 10) added 0.2 mg/g MK4. Body weight gain was followed weekly. Morphology of aortic valves and liver was assessed with immunohistochemistry. Plasma cholesterol levels and cytokines from hepatic tissue were assessed in the end of the study. Hepatic gene expression of lipid metabolism regulating genes were assessed after 18 h diet. MK4 exacerbated the lipoprotein lipid profile without affecting aortic valve morphology in hypercholesterolemic LDLr−/− ApoB100/100 mice. The MK4-containing WD diet increased plasma levels of LDL and triglycerides, hepatic steatosis, and mRNA expression of genes required for triglyceride and cholesterol synthesis. MK4 diminished levels of several cytokines and chemokines in liver, including IL-6, TNFα and MCP1, as measured by hepatic cytokine array. Consequently, MK4 may exert non-beneficial effects on circulating lipid levels, especially in hypercholesterolemic individuals.

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Section: Discussionmentioning

confidence: 99%

Menaquinone 4 increases plasma lipid levels in hypercholesterolemic mice

Weisell

Ruotsalainen

Näpänkangas

et al. 2021

Sci Rep

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“…This suggests that other ligands of SXR/PXR could also induce HAVIC calcification. In line with this, MK4, which has also been shown to be a ligand of SXR/PXR [ 67 , 68 ], was shown to dose-dependently accelerate HAVIC calcification [ 69 ]. MK4 and warfarin exhibit structural similarity and were therefore thought to compete for the same binding site on SXR/PXR.…”

Section: Role Of Nuclear Receptors In Vascular Calcificationmentioning

confidence: 94%

“…MK4 and warfarin exhibit structural similarity and were therefore thought to compete for the same binding site on SXR/PXR. However, surprisingly, MK4 seems to accelerate warfarin-induced HAVIC calcification [ 69 ]. Warfarin, SR-12813, and MK4 were all three shown to induce expression of BMP-2 (a calcification inducer of the bone morphogenetic proteins, members of the transforming growth factor β family) leading to enhanced TNAP/ALP activity [ 65 , 69 ].…”

Section: Role Of Nuclear Receptors In Vascular Calcificationmentioning

confidence: 99%

Roles of Nuclear Receptors in Vascular Calcification

Chinetti-Gbaguidi

Neels

2021

IJMS

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Vascular calcification is defined as an inappropriate accumulation of calcium depots occurring in soft tissues, including the vascular wall. Growing evidence suggests that vascular calcification is an actively regulated process, sharing similar mechanisms with bone formation, implicating both inhibitory and inducible factors, mediated by osteoclast-like and osteoblast-like cells, respectively. This process, which occurs in nearly all the arterial beds and in both the medial and intimal layers, mainly involves vascular smooth muscle cells. In the vascular wall, calcification can have different clinical consequences, depending on the pattern, localization and nature of calcium deposition. Nuclear receptors are transcription factors widely expressed, activated by specific ligands that control the expression of target genes involved in a multitude of pathophysiological processes, including metabolism, cancer, inflammation and cell differentiation. Some of them act as drug targets. In this review we describe and discuss the role of different nuclear receptors in the control of vascular calcification.

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“…To visualize the degree of calcification, cells were seeded in 24-well plates and grown to 70–80% confluence; cells were treated with 3 mM Pi and then incubated for 1, 3, 5, 7, and 10 days. 27,28 Briefly, cells were fixed with 4% paraformaldehyde for 10 min at room temperature and stained for 10 min with 40 mM Alizarin Red S (pH 4.2; Sigma-Aldrich) at room temperature. The calcium deposits were quantified using a colorimetric kit from BioAssay Systems (Hayward, CA, USA) after solubilization of the deposits for 4 h at room temperature with 0.6 N HCl.…”

Section: Methodsmentioning

confidence: 99%

Calcifying characteristics of peripheral vascular smooth muscle cells of chronic kidney disease patients with critical limb ischemia

et al. 2021

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The role of vascular smooth muscle cells (VSMCs) in vascular calcification, which is related to chronic kidney disease (CKD), has been studied in greater detail in the major arteries relative to the peripheral arteries. We compared the calcifying characteristics of peripheral VSMCs relative to non-pathologic major VSMCs in patients with severe peripheral artery disease (PAD). We isolated peripheral VSMCs from the posterior tibial artery of 10 patients with CKD who underwent below-knee amputation for critical limb ischemia (CLI). Using normal human aortic VSMCs as a control group, we cultured the cells in normal and high phosphate media for 10 days, and subsequently tested by immunofluorescence staining. We compared the calcification levels between the two groups using various assays, tests for cell viability, and scanning electron microscopy. As a result, calcification of pathologic peripheral VSMCs increased significantly with time ( p = 0.028) and was significantly higher than that in human aortic VSMCs in calcium assays ( p = 0.043). Dead cells in the pathologic VSMC group were more distinct in high phosphate media than in human aortic VSMCs. In conclusion, VSMCs from the peripheral artery of patients with severe CKD and CLI who underwent amputation surgery showed marked calcifying characteristics compared to normal human aortic VSMCs.

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Menaquinone-4 Accelerates Calcification of Human Aortic Valve Interstitial Cells in High-Phosphate Medium through PXR

Cited by 11 publications

References 39 publications

Menaquinone 4 increases plasma lipid levels in hypercholesterolemic mice

Menaquinone 4 increases plasma lipid levels in hypercholesterolemic mice

Roles of Nuclear Receptors in Vascular Calcification

Calcifying characteristics of peripheral vascular smooth muscle cells of chronic kidney disease patients with critical limb ischemia

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