High-Dose Menaquinone-7 Supplementation Reduces Cardiovascular Calcification in a Murine Model of Extraosseous Calcification

Daniel Scheiber, Verena Veulemans, Patrick Horn, Martijn L Chatrou, Sebastian A Potthoff, Malte Kelm, Leon J Schurgers, Ralf Westenfeld, Daniel Scheiber, Verena Veulemans, Patrick Horn, Martijn L Chatrou, Sebastian A Potthoff, Malte Kelm, Leon J Schurgers, Ralf Westenfeld

Abstract

Cardiovascular calcification is prevalent in the aging population and in patients with chronic kidney disease (CKD) and diabetes mellitus, giving rise to substantial morbidity and mortality. Vitamin K-dependent matrix Gla-protein (MGP) is an important inhibitor of calcification. The aim of this study was to evaluate the impact of high-dose menaquinone-7 (MK-7) supplementation (100 µg/g diet) on the development of extraosseous calcification in a murine model. Calcification was induced by 5/6 nephrectomy combined with high phosphate diet in rats. Sham operated animals served as controls. Animals received high or low MK-7 diets for 12 weeks. We assessed vital parameters, serum chemistry, creatinine clearance, and cardiac function. CKD provoked increased aortic (1.3 fold; p < 0.05) and myocardial (2.4 fold; p < 0.05) calcification in line with increased alkaline phosphatase levels (2.2 fold; p < 0.01). MK-7 supplementation inhibited cardiovascular calcification and decreased aortic alkaline phosphatase tissue concentrations. Furthermore, MK-7 supplementation increased aortic MGP messenger ribonucleic acid (mRNA) expression (10-fold; p < 0.05). CKD-induced arterial hypertension with secondary myocardial hypertrophy and increased elastic fiber breaking points in the arterial tunica media did not change with MK-7 supplementation. Our results show that high-dose MK-7 supplementation inhibits the development of cardiovascular calcification. The protective effect of MK-7 may be related to the inhibition of secondary mineralization of damaged vascular structures.

Keywords: cardiovascular calcification; chronic kidney disease; matrix Gla-protein; menaquinone-7; vitamin K2.

Figures

Figure 1
Figure 1
Body weight in grams (g). Body weight of animals was measured repetitively during 12 weeks of study protocol. Experimental animals were not fully grown at start of the experiment; however, all animals gained weight significantly. During the experiment, control animals (Co; Co-K2) gained significantly more weight compared to CKD and CKD-K2 animals. Co = control group; Co-K2 = MK-7 supplemented control group; CKD = 5/6 nephrectomized group; CKD-K2 = MK-7 supplemented 5/6 nephrectomized group; g = grams. Significant differences: ***p < 0.001.
Figure 2
Figure 2
Aortic calcium content. Measurement of aortic calcium content was performed by atomic absorption spectrometry and expressed as μg Ca/mg dry weight tissue. CKD animals display a significant increase in aortic calcium content compared to Co-K2 animals. Co = control group; Co-K2 = MK-7 supplemented control group; CKD = 5/6 nephrectomized group; CKD-K2 = MK-7 supplemented 5/6 nephrectomized group; mg = milligrams; µg = micrograms. Significant differences: *p < 0.05.
Figure 3
Figure 3
Alkaline phosphatase (ALP) in aortic tissues. ALP was measured to detect local vascular osteochondrogenic activity. Positive staining for ALP is expressed as product score: ALP-positive staining areal × intensity. ALP-product-score is significantly increased in CKD animals as compared to Co animals. Co = control group; Co-K2 = MK-7 supplemented control group; CKD = 5/6 nephrectomized group; CKD-K2 = MK-7 supplemented 5/6 nephrectomized group. Significant differences: **p < 0.01.
Figure 4
Figure 4
Myocardial calcium content. Measurement of myocardial calcium content using atomic absorption spectrometry in μg Ca/mg dry weight tissue. CKD animals display a significantly increased myocardial calcium content compared to Co animals. Co = control group; Co-K2 = MK-7 supplemented control group; CKD = 5/6 nephrectomized group; CKD-K2 = MK-7 supplemented 5/6 nephrectomized group; mg = milligrams; µg = micrograms. Significant differences: *p < 0.05.
Figure 5
Figure 5
Renal calcification. Von Kossa positive staining area expressed as percentage of tissue area. In 5/6 nephrectomized animals significantly more von Kossa positivity was measured as compared to the control groups. No differences were seen between CKD and CKD-K2 treated groups. Co = control group; Co-K2 = MK-7 supplemented control group; CKD = 5/6 nephrectomized group; CKD-K2 = MK-7 supplemented 5/6 nephrectomized group. Significant differences: **p < 0.01, ***p < 0.001.
Figure 6
Figure 6
Representative sections of von Kossa stained tissue samples. Microscopically visible von Kossa positive staining was only detected in kidney tissue samples of CKD and CDK-K2 animals. Magnification 40×; Counterstain: nuclear fast red; Co = control group; Co-K2 = MK-7 supplemented control group; CKD = 5/6 nephrectomized group; CKD-K2 = MK-7 supplemented 5/6 nephrectomized group.
Figure 7
Figure 7
Elastic fiber breaking points. Elastica van Gieson (EvG) staining of aortic tissue samples with focus on elastic fiber breaking points. CKD animals display significantly more elastic fiber breaking points compared to Co animals. Co = control group; Co-K2 = MK-7 supplemented control group; CKD = 5/6 nephrectomized group; CKD-K2 = MK-7 supplemented 5/6 nephrectomized group. Significant differences: ***p < 0.001.
Figure 8
Figure 8
Proliferative response. Ratio of positive staining area for Ki67 per DAPI positive staining area in % per mm2. DAPI values do not differ significantly between groups. CKD animals display significantly more Ki67 positive staining area per DAPI positive staining area compared to Co animals. Co = control group; Co-K2 = MK-7 supplemented control group; CKD = 5/6 nephrectomized group; CKD-K2 = MK-7 supplemented 5/6 nephrectomized group; mm = millimeters. Significant differences: ***p < 0.001.
Figure 9
Figure 9
Systolic and diastolic blood pressure. Systolic and diastolic blood pressure after 12 weeks of treatment. CKD animals developed significantly increased systolic and diastolic blood pressure values compared to controls. Co = control group; Co-K2 = MK-7 supplemented control group; CKD = 5/6 nephrectomized group; CKD-K2 = MK-7 supplemented 5/6 nephrectomized group; mmHg = millimeters of mercury. Significant differences: *p < 0.05, **p < 0.01.
Figure 10
Figure 10
Echocardiography of diastolic interventricular septum diameter (LVISD) in cm. Echocardiography was performed in all animals after 12 weeks of study protocol. CKD animals developed significantly increased LVISD compared to controls. Co = control group; Co-K2 = MK-7 supplemented control group; CKD = 5/6 nephrectomized group; CKD-K2 = MK-7 supplemented 5/6 nephrectomized group; cm = centimeters. Significant differences: *p < 0.05, **p < 0.01.
Figure 11
Figure 11
Aortic gene expression. The effect of CKD and MK-7 supplementation on aortic gene expression of calcification modifiers as x-fold induction compared to control group. Red columns depict pro-calcific changes, while alterations associated with potential calcification inhibition are assigned with blue columns. (a) In CKD animals SM22α expression is significantly decreased, whereas MGP expression is non-significantly decreased as compared to Co animals. (b) In Co-K2 animals MGP mRNA concentration is significantly increased, whereas POST mRNA concentration is significantly decreased compared to Co animals. (c) In CKD-K2 animals MGP mRNA concentration is significantly and SM22α mRNA concentration is tendentially increased compared to Co animals. Co = control group; Co-K2 = MK-7 supplemented control group; CKD = 5/6 nephrectomized group; CKD-K2 = MK-7 supplemented 5/6 nephrectomized group; MGP = matrix Gla-protein; POST = periostin; BMP-2 = bone morphogenetic protein 2. Significant differences: *p < 0.05, **p < 0.01.

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