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Vascul Pharmacol. 2019 Nov - Dec;122-123:106581. doi: 10.1016/j.vph.2019.106581. Epub 2019 Aug 14.

Vitamin K2-MK-7 improves nitric oxide-dependent endothelial function in ApoE/LDLR-/- mice.

Author information

1
Jagiellonian University, Jagiellonian Centre for Experimental Therapeutics (JCET), Bobrzynskiego 14, 30-348 Krakow, Poland; Jagiellonian University Medical College, Faculty of Medicine, Chair of Pharmacology, Grzegorzecka 16, 31-531 Krakow, Poland. Electronic address: anna.bar@jcet.eu.
2
Jagiellonian University, Jagiellonian Centre for Experimental Therapeutics (JCET), Bobrzynskiego 14, 30-348 Krakow, Poland. Electronic address: kamil.kus@jcet.eu.
3
University of Agriculture H. Kollataja in Krakow, Department of Human Nutrition, Faculty of Food Technology, Balicka 122, 30-149 Krakow, Poland.
4
Jagiellonian University, Jagiellonian Centre for Experimental Therapeutics (JCET), Bobrzynskiego 14, 30-348 Krakow, Poland. Electronic address: bartosz.proniewski@jcet.eu.
5
Jagiellonian University, Jagiellonian Centre for Experimental Therapeutics (JCET), Bobrzynskiego 14, 30-348 Krakow, Poland. Electronic address: magdalena.sternak@jcet.eu.
6
Jagiellonian University, Jagiellonian Centre for Experimental Therapeutics (JCET), Bobrzynskiego 14, 30-348 Krakow, Poland. Electronic address: kamil.przyborowski@jcet.eu.
7
Maastricht University, Cardiovascular Research Institute Maastricht, the Netherlands; Synapse BV, the Netherlands.
8
Jagiellonian University, Jagiellonian Centre for Experimental Therapeutics (JCET), Bobrzynskiego 14, 30-348 Krakow, Poland. Electronic address: barbara.sitek@jcet.eu.
9
Jagiellonian University, Jagiellonian Centre for Experimental Therapeutics (JCET), Bobrzynskiego 14, 30-348 Krakow, Poland; Jagiellonian University Medical College, Faculty of Medicine, Chair of Pharmacology, Grzegorzecka 16, 31-531 Krakow, Poland. Electronic address: brygida.marczyk@jcet.eu.
10
Jagiellonian University, Jagiellonian Centre for Experimental Therapeutics (JCET), Bobrzynskiego 14, 30-348 Krakow, Poland. Electronic address: agnieszka.jasztal@jcet.eu.
11
Institute of Nuclear Physics Polish Academy of Sciences, Department of Magnetic Resonance Imaging, Radzikowskiego 152, 31-342 Kraków, Poland. Electronic address: Tomasz.Skorka@ifj.edu.pl.
12
University of Agriculture H. Kollataja in Krakow, Department of Human Nutrition, Faculty of Food Technology, Balicka 122, 30-149 Krakow, Poland. Electronic address: magdalena.franczyk-zarow@urk.edu.pl.
13
University of Agriculture H. Kollataja in Krakow, Department of Human Nutrition, Faculty of Food Technology, Balicka 122, 30-149 Krakow, Poland. Electronic address: rkostogrys@ar.krakow.pl.
14
Jagiellonian University, Jagiellonian Centre for Experimental Therapeutics (JCET), Bobrzynskiego 14, 30-348 Krakow, Poland; Jagiellonian University Medical College, Faculty of Medicine, Chair of Pharmacology, Grzegorzecka 16, 31-531 Krakow, Poland. Electronic address: stefan.chlopicki@jcet.eu.

Abstract

Although, vitamin K2 displays vasoprotective effects, it is still not known whether K2 treatment improves endothelial function. In ApoE/LDLR-/- mice at the stage prior to atherosclerosis development, four-week treatment with K2-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 K2-MK-7 (0.5; 5 mg/kg) resulted in a dose-dependent increase in plasma K2-MK-7 and K2-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 K2-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 K2-MK-7 also reduced media thickness in the brachiocephalic artery, but did not modify atherosclerotic plaque size. In conclusion, K2-MK-7 improves NO-dependent endothelial function in ApoE/LDLR-/- mice. This study, identifies the endothelial profile of the pharmacological activity of vitamin K2, which has not been previously described.

KEYWORDS:

Atherosclerosis; Endothelial function; MRI; Menaquinone-7

PMID:
31421222
DOI:
10.1016/j.vph.2019.106581

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