Vitamin K-2-MK-7 improves nitric oxide-dependent endothelial function in ApoE/LDLR-/- mice

Anna Bar; Kamil Kus; Angelika Manterys; Bartosz Proniewski; Magdalena Sternak; Kamil Przyborowski; Martijn Moorlag; Barbara Sitek; Brygida Marczyk; Agnieszka Jasztal; Tomasz Skorka; Magdalena Franczyk-Zarow; Renata B. Kostogrys; Stefan Chlopicki

doi:10.1016/j.vph.2019.106581

Vitamin K-2-MK-7 improves nitric oxide-dependent endothelial function in ApoE/LDLR-/- mice

Anna Bar, Kamil Kus, Angelika Manterys, Bartosz Proniewski, Magdalena Sternak, Kamil Przyborowski, Martijn Moorlag, Barbara Sitek, Brygida Marczyk, Agnieszka Jasztal, Tomasz Skorka, Magdalena Franczyk-Zarow, Renata B. Kostogrys, Stefan Chlopicki^*

^*Corresponding author for this work

Research output: Contribution to journal › Article › Academic › peer-review

Abstract

Although, vitamin K-2 displays vasoprotective effects, it is still not known whether K-2 treatment improves endothelial function.

In ApoE/LDLR-/- mice at the stage prior to atherosclerosis development, four-week treatment with K-2-MK-7, given at a low dose (0.05 mg/kg), improved acetylcholine- and flow-induced, endothelium-dependent vasodilation in aorta or in femoral artery, as assessed by MRI in vivo. This effect was associated with an increased NO production, as evidenced by EPR measurements in ex vivo aorta. Treatment with higher doses of K-2-MK-7 (0.5; 5 mg/kg) resulted in a dose-dependent increase in plasma K-2-MK-7 and K-2-MK-4 concentration, without further improvement in endothelial function. In ApoE/LDLR-/- mice with developed atherosclerotic plaques, treatment with a low (0.03 mg/kg) or high (10 mg/kg) dose of K-2-MK-7 resulted in a similar degree of endothelium-dependent vasodilation improvement and increase in plasma nitrate concentration, what was not associated with changes in thrombin generation as measured by CAT. Both doses of K-2-MK-7 also reduced media thickness in the brachiocephalic artery, but did not modify atherosclerotic plaque size.

In conclusion, K-2-MK-7 improves NO-dependent endothelial function in ApoE/LDLR-/- mice. This study, identifies the endothelial profile of the pharmacological activity of vitamin K-2, which has not been previously described.

Original language	English
Article number	106581
Number of pages	13
Journal	Vascular Pharmacology
Volume	122-123
DOIs	https://doi.org/10.1016/j.vph.2019.106581
Publication status	Published - 2019

Keywords

Endothelial function
Atherosclerosis
MRI
Menaquinone-7
DENSITY-LIPOPROTEIN RECEPTOR
GAMMA-CARBOXYGLUTAMIC ACID
VASCULAR CALCIFICATION
THROMBIN GENERATION
ARTERIAL STIFFNESS
LOW CARBOHYDRATE
DOUBLE-BLIND
ATHEROSCLEROSIS
SUPPLEMENTATION
DYSFUNCTION

Access to Document

10.1016/j.vph.2019.106581

Cite this

Bar, A., Kus, K., Manterys, A., Proniewski, B., Sternak, M., Przyborowski, K., Moorlag, M., Sitek, B., Marczyk, B., Jasztal, A., Skorka, T., Franczyk-Zarow, M., Kostogrys, R. B., & Chlopicki, S. (2019). Vitamin K-2-MK-7 improves nitric oxide-dependent endothelial function in ApoE/LDLR-/- mice. Vascular Pharmacology, 122-123, Article 106581. https://doi.org/10.1016/j.vph.2019.106581

@article{b52f5e55d1a347159a0b8ebccf61ae5d,

title = "Vitamin K-2-MK-7 improves nitric oxide-dependent endothelial function in ApoE/LDLR-/- mice",

abstract = "Although, vitamin K-2 displays vasoprotective effects, it is still not known whether K-2 treatment improves endothelial function.In ApoE/LDLR-/- mice at the stage prior to atherosclerosis development, four-week treatment with K-2-MK-7, given at a low dose (0.05 mg/kg), improved acetylcholine- and flow-induced, endothelium-dependent vasodilation in aorta or in femoral artery, as assessed by MRI in vivo. This effect was associated with an increased NO production, as evidenced by EPR measurements in ex vivo aorta. Treatment with higher doses of K-2-MK-7 (0.5; 5 mg/kg) resulted in a dose-dependent increase in plasma K-2-MK-7 and K-2-MK-4 concentration, without further improvement in endothelial function. In ApoE/LDLR-/- mice with developed atherosclerotic plaques, treatment with a low (0.03 mg/kg) or high (10 mg/kg) dose of K-2-MK-7 resulted in a similar degree of endothelium-dependent vasodilation improvement and increase in plasma nitrate concentration, what was not associated with changes in thrombin generation as measured by CAT. Both doses of K-2-MK-7 also reduced media thickness in the brachiocephalic artery, but did not modify atherosclerotic plaque size.In conclusion, K-2-MK-7 improves NO-dependent endothelial function in ApoE/LDLR-/- mice. This study, identifies the endothelial profile of the pharmacological activity of vitamin K-2, which has not been previously described.",

keywords = "Endothelial function, Atherosclerosis, MRI, Menaquinone-7, DENSITY-LIPOPROTEIN RECEPTOR, GAMMA-CARBOXYGLUTAMIC ACID, VASCULAR CALCIFICATION, THROMBIN GENERATION, ARTERIAL STIFFNESS, LOW CARBOHYDRATE, DOUBLE-BLIND, ATHEROSCLEROSIS, SUPPLEMENTATION, DYSFUNCTION",

author = "Anna Bar and Kamil Kus and Angelika Manterys and Bartosz Proniewski and Magdalena Sternak and Kamil Przyborowski and Martijn Moorlag and Barbara Sitek and Brygida Marczyk and Agnieszka Jasztal and Tomasz Skorka and Magdalena Franczyk-Zarow and Kostogrys, {Renata B.} and Stefan Chlopicki",

note = "Funding Information: This work was supported by Polish National Science Centre grants: OPUS Grant No. 2018/29/B/NZ7/01684 , PRELUDIUM Grant No. 2016/23/N/NZ5/00595 and partially by Kaydence Pharma . The authors would like to thank Agnieszka Zakrzewska for expert technical assistance and with measurements of nitrite and nitrate concentration in plasma. We would like to thank Leon Schurgers (CARIM School for Cardiovascular Diseases, Maastricht University, the Netherlands) for discussions. We would also like to thank to Dr. Bas de Laat from Synapse BV for methodological support in CAT and providing CAT reagents. Funding Information: This work was supported by Polish National Science Centre grants: OPUS Grant No. 2018/29/B/NZ7/01684, PRELUDIUM Grant No. 2016/23/N/NZ5/00595 and partially by Kaydence Pharma. The authors would like to thank Agnieszka Zakrzewska for expert technical assistance and with measurements of nitrite and nitrate concentration in plasma. We would like to thank Leon Schurgers (CARIM School for Cardiovascular Diseases, Maastricht University, the Netherlands) for discussions. We would also like to thank to Dr. Bas de Laat from Synapse BV for methodological support in CAT and providing CAT reagents. None. Publisher Copyright: {\textcopyright} 2019 Elsevier Inc.",

year = "2019",

doi = "10.1016/j.vph.2019.106581",

language = "English",

volume = "122-123",

journal = "Vascular Pharmacology",

issn = "1537-1891",

publisher = "Elsevier Science",

}

TY - JOUR

T1 - Vitamin K-2-MK-7 improves nitric oxide-dependent endothelial function in ApoE/LDLR-/- mice

AU - Bar, Anna

AU - Kus, Kamil

AU - Manterys, Angelika

AU - Proniewski, Bartosz

AU - Sternak, Magdalena

AU - Przyborowski, Kamil

AU - Moorlag, Martijn

AU - Sitek, Barbara

AU - Marczyk, Brygida

AU - Jasztal, Agnieszka

AU - Skorka, Tomasz

AU - Franczyk-Zarow, Magdalena

AU - Kostogrys, Renata B.

AU - Chlopicki, Stefan

N1 - Funding Information: This work was supported by Polish National Science Centre grants: OPUS Grant No. 2018/29/B/NZ7/01684 , PRELUDIUM Grant No. 2016/23/N/NZ5/00595 and partially by Kaydence Pharma . The authors would like to thank Agnieszka Zakrzewska for expert technical assistance and with measurements of nitrite and nitrate concentration in plasma. We would like to thank Leon Schurgers (CARIM School for Cardiovascular Diseases, Maastricht University, the Netherlands) for discussions. We would also like to thank to Dr. Bas de Laat from Synapse BV for methodological support in CAT and providing CAT reagents. Funding Information: This work was supported by Polish National Science Centre grants: OPUS Grant No. 2018/29/B/NZ7/01684, PRELUDIUM Grant No. 2016/23/N/NZ5/00595 and partially by Kaydence Pharma. The authors would like to thank Agnieszka Zakrzewska for expert technical assistance and with measurements of nitrite and nitrate concentration in plasma. We would like to thank Leon Schurgers (CARIM School for Cardiovascular Diseases, Maastricht University, the Netherlands) for discussions. We would also like to thank to Dr. Bas de Laat from Synapse BV for methodological support in CAT and providing CAT reagents. None. Publisher Copyright: © 2019 Elsevier Inc.

PY - 2019

Y1 - 2019

N2 - Although, vitamin K-2 displays vasoprotective effects, it is still not known whether K-2 treatment improves endothelial function.In ApoE/LDLR-/- mice at the stage prior to atherosclerosis development, four-week treatment with K-2-MK-7, given at a low dose (0.05 mg/kg), improved acetylcholine- and flow-induced, endothelium-dependent vasodilation in aorta or in femoral artery, as assessed by MRI in vivo. This effect was associated with an increased NO production, as evidenced by EPR measurements in ex vivo aorta. Treatment with higher doses of K-2-MK-7 (0.5; 5 mg/kg) resulted in a dose-dependent increase in plasma K-2-MK-7 and K-2-MK-4 concentration, without further improvement in endothelial function. In ApoE/LDLR-/- mice with developed atherosclerotic plaques, treatment with a low (0.03 mg/kg) or high (10 mg/kg) dose of K-2-MK-7 resulted in a similar degree of endothelium-dependent vasodilation improvement and increase in plasma nitrate concentration, what was not associated with changes in thrombin generation as measured by CAT. Both doses of K-2-MK-7 also reduced media thickness in the brachiocephalic artery, but did not modify atherosclerotic plaque size.In conclusion, K-2-MK-7 improves NO-dependent endothelial function in ApoE/LDLR-/- mice. This study, identifies the endothelial profile of the pharmacological activity of vitamin K-2, which has not been previously described.

AB - Although, vitamin K-2 displays vasoprotective effects, it is still not known whether K-2 treatment improves endothelial function.In ApoE/LDLR-/- mice at the stage prior to atherosclerosis development, four-week treatment with K-2-MK-7, given at a low dose (0.05 mg/kg), improved acetylcholine- and flow-induced, endothelium-dependent vasodilation in aorta or in femoral artery, as assessed by MRI in vivo. This effect was associated with an increased NO production, as evidenced by EPR measurements in ex vivo aorta. Treatment with higher doses of K-2-MK-7 (0.5; 5 mg/kg) resulted in a dose-dependent increase in plasma K-2-MK-7 and K-2-MK-4 concentration, without further improvement in endothelial function. In ApoE/LDLR-/- mice with developed atherosclerotic plaques, treatment with a low (0.03 mg/kg) or high (10 mg/kg) dose of K-2-MK-7 resulted in a similar degree of endothelium-dependent vasodilation improvement and increase in plasma nitrate concentration, what was not associated with changes in thrombin generation as measured by CAT. Both doses of K-2-MK-7 also reduced media thickness in the brachiocephalic artery, but did not modify atherosclerotic plaque size.In conclusion, K-2-MK-7 improves NO-dependent endothelial function in ApoE/LDLR-/- mice. This study, identifies the endothelial profile of the pharmacological activity of vitamin K-2, which has not been previously described.

KW - Endothelial function

KW - Atherosclerosis

KW - MRI

KW - Menaquinone-7

KW - DENSITY-LIPOPROTEIN RECEPTOR

KW - GAMMA-CARBOXYGLUTAMIC ACID

KW - VASCULAR CALCIFICATION

KW - THROMBIN GENERATION

KW - ARTERIAL STIFFNESS

KW - LOW CARBOHYDRATE

KW - DOUBLE-BLIND

KW - ATHEROSCLEROSIS

KW - SUPPLEMENTATION

KW - DYSFUNCTION

U2 - 10.1016/j.vph.2019.106581

DO - 10.1016/j.vph.2019.106581

M3 - Article

C2 - 31421222

SN - 1537-1891

VL - 122-123

JO - Vascular Pharmacology

JF - Vascular Pharmacology

M1 - 106581

ER -