Vitamin K dependent Matrix Gla Protein as a Marker for Vascular Calcification in Chronic Kidney Disease: Study
One of the major causes of mortality in CKD patients is cardiovascular complications. Vascular calcification, regarded to be a common cause of cardiovascular mortality, is an active process directly regulated by vitamin K dependent proteins (VKDPs), and manifested by the deposition of calcium phosphate complexes, specifically in the medial or intimal vessel walls, mostly in the form of hydroxyapatite. (1)
At present, one of Vitamin K-dependent proteins has gained immense attention: matrix - carboxyglutamate (Gla) protein (MGP), a potent inhibitor of calcification. MPG is usually present in cartilage and the vascular walls, where it is synthesized by chondrocytes and vascular smooth muscle cells (VSMCs), respectively. (2, 3)
Gla residues can bind calcium both in solution and in calcium salt crystals, which is thought to be associated with the ability of MGP to inhibit crystal growth (4). It is well-documented hat MGP only exerts its anti-calcification activity after posttranslational -glutamyl carboxylation of five glutamate residues—a crucial activation step that depends on the availability of vitamin K (5).
Previous studies have clearly shown that deficiency of vitamin K, mainly nutritional deficiency, results in under-carboxylation of MGP and loss of its biological function [6]. Further research has proved that this inactive un-carboxylated MGP (ucMGP) accumulates at sites of arterial calcification and thus has been hypothesized to be an active marker of Cardiovascular Calcification.
It has also been highlighted that Vitamin K2 i.e. menaquinone is the most prevalent form of vitamin K in non-hepatic tissue. Since MGP is a peripheral protein, vitamin K2 is the vitamin mostly available to carboxylate MGP(1). Taking into account the growing evidence suggesting the profound effects of vitamin K2 in reducing vascular calcification, it was found to decrease arterial calcification on cultured bovine aortic smooth muscle cells. (7) In the Rotterdam study, (8) Dietary VK2 intake was associated with a lower occurrence of aortic calcification and coronary heart disease in patients. Similarly, a study on postmenopausal women found a lower incidence of coronary calcification with increased consumption of VK2 or menaquinones, particularly MK-4. (9)
Recognizing such role of vitamin K2, the International Life Sciences Institute (ILSI Europe), recently recommended taking VK2, also to VK1, into consideration when calculating the daily recommended value of vitamin K .(10)
With this background, in 2010, a study was performed by Leon J. Schurgers et al from the Cardiovascular Research Institute, University of Maastricht, the Netherlands to (1) determine plasma levels of the inactive, dephosphorylated, uncarboxylated MGP (dp-ucMGP) in a cohort of patients at different stages of chronic kidney disease (CKD) and (2) evaluate the association between dp-ucMGP levels on one hand and aortic calcification and mortality on the other.(11)
The findings were published In the Clinical Journal of the American Society of Nephrology.
Methodology
Over 18 months (from January 2006 to June 2007),107 patients (avg age 67 years; 60% male; 32% at CKD stages 2 to 3, 31% at stages 4 to 5, 37% at stage 5D) were assayed for dp-ucMGP and underwent multislice spiral computed tomography scans to quantify aortic calcification at baseline. Hemodialysis patients were preferentially seen on a dialysis-free day or, if this was not possible, the morning before the dialysis session.
They were prospectively monitored for mortality. Previous cardiovascular disease was defined as a history of any of the following events: myocardial infarction, stroke, heart failure, angina pectoris, or surgical procedures for angina or coronary/peripheral artery disease (including percutaneous transluminal angioplasty).
Plasma levels of dp-ucMGP were determined using a recently developed sandwich ELISA involving two anti-MGP monoclonal antibodies. The synthetic peptide dpMGP3-15-(AADO)- ucMGP35-54 was used as a standard.
On data analysis, the following key facts emerged.
ï‚· Plasma dp-ucMGP levels augmented progressively with CKD stage, with a significant difference from CKD stage 4.
ï‚· CKD stage, hemoglobin, age, and coumarin use were independently associated with plasma dp-ucMGP levels.
ï‚· Furthermore, plasma dp-ucMGP and age were positively and independently associated with the aortic calcification score.
ï‚· During follow-up (802 311 days), 34 patients died (20 from cardiovascular events). In crude analysis, [plasma dp-ucMGP] > 921 pM was associated with overall mortality; this association was lost after adjusting for both age and the calculated propensity score.
The authors further observed that,
1. Their findings indicated that elevation of serum levels of the inactive form of MGP parallels the progression of CKD and thus seems to be an important contributor to (or even a biomarker of) the severity of the VC frequently observed in the CKD setting. The high dp-ucMGP levels could reflect a low dietary intake of vitamin K, resulting in lower metabolic availability and thus less MGP -glutamyl carboxylation in patients with more advanced CKD.
2. It seemed possible that plasma dp-ucMGP is simply a biomarker that reflects the VC burden. In theory, higher levels of the inactive form of MGP would initially favor VC. This high calcification burden would lead to a burst in MGP production, further exhausting vitamin K stores, limiting MGP activation, and resulting in additional VC.
From the results, the research team opined that" Plasma dp-ucMGP increased progressively in a CKD setting and was associated with the severity of aortic calcification. Plasma dp-ucMGP could thus be a surrogate marker for vascular calcification in CKD."
With these findings, it is safe to say that Vitamin K2 has promising potential to be used as treatment or prevention for the development of vascular calcification, especially in at-risk patient groups of CKD, with a high incidence of calcification or vitamin K deficiency. Clinical trials looking into the effect of Vitamin K2 on activated or inactivated MGP levels in blood with vascular calcification and its beneficial cardiovascular effects will help elucidate its potential role as a therapeutic strategy.
The above article has been published by Medical Dialogues under the MD Brand Connect Initiative. For more details on Vitamin K, click here
References
1. El Asmar, M. S., Naoum, J. J., & Arbid, E. J. (2014). Vitamin k dependent proteins and the role of vitamin k2 in the modulation of vascular calcification: a review. Oman medical journal, 29(3), 172–177. https://doi.org/10.5001/omj.2014.44
2. Luo G, D'Souza R, Hogue D, Karsenty G: The matrix Gla protein gene is a marker of the chondrogenesis cell lineage during mouse development. J Bone Miner Res 1995;10: 325–334.
3. Wallin R, Cain D, Sane DC: Matrix Gla protein synthesis and gamma-carboxylation in the aortic vessel wall and proliferating vascular smooth muscle cells – a cell system which resembles the system in bone cells. Thromb Haemost 1999;82:1764–1767.
4. Price PA, Faus SA, Williamson MK: Warfarin causes rapid calcification of the elastic lamellae in rat arteries and heart valves. Arterioscler Thromb Vasc Biol 1998;18:1400- 1407.
5. Berkner KL, Runge KW: The physiology of vitamin K nutriture and vitamin K- dependent protein function in atherosclerosis. J Thromb Haemost 2004;2:2118–2132.
6. Molecular mechanisms mediating vascular calcification: role of matrix Gla protein.Proudfoot D, Shanahan CM Nephrology (Carlton). 2006 Oct; 11(5):455-61
7. Saito E, Wachi H, Sato F, Sugitani H, Seyama Y. Treatment with vitamin k(2) combined with bisphosphonates synergistically inhibits calcification in cultured smooth muscle cells. J Atheroscler Thromb 2007. Dec;14(6):317-324 10.5551/jat.E501
8. Dietary intake of menaquinone is associated with a reduced risk of coronary heart disease: the Rotterdam Study.Geleijnse JM, Vermeer C, Grobbee DE, Schurgers LJ, Knapen MH, van der Meer IM, Hofman A, Witteman JC J Nutr. 2004 Nov; 134(11):3100-5.
9. High dietary menaquinone intake is associated with reduced coronary calcification. Beulens JW, Bots ML, Atsma F, Bartelink ML, Prokop M, Geleijnse JM, Witteman JC, Grobbee DE, van der Schouw YT Atherosclerosis. 2009 Apr; 203(2):489-93.
10. The role of menaquinones (vitamin Kâ‚‚) in human health. Beulens JW, Booth SL, van den Heuvel EG, Stoecklin E, Baka A, Vermeer C Br J Nutr. 2013 Oct; 110(8):1357-68.
11. Schurgers LJ, Barreto DV, Barreto FC, Liabeuf S, Renard C, Magdeleyns EJ, Vermeer C, Choukroun G, Massy ZA: The circulating inactive form of matrix Gla protein is a surrogate marker for vascular calcification in chronic kidney disease: A preliminary report. Clin J Am Soc Nephrol 5: 568 –575, 2010
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