This Is MS Multiple Sclerosis Knowledge & Support Community

1: J Vasc Res. 2008;45(5):427-36. Epub 2008 Apr 10. Links
The circulating inactive form of matrix Gla Protein (ucMGP) as a biomarker for cardiovascular calcification.Cranenburg EC, Vermeer C, Koos R, Boumans ML, Hackeng TM, Bouwman FG, Kwaijtaal M, Brandenburg VM, Ketteler M, Schurgers LJ.
VitaK, Maastricht University, Maastricht, The Netherlands.

OBJECTIVE: Matrix gamma-carboxyglutamate (Gla) protein (MGP) is a vitamin K-dependent protein and a strong inhibitor of vascular calcification. Vitamin K deficiency leads to inactive uncarboxylated MGP (ucMGP), which accumulates at sites of arterial calcification. We hypothesized that as a result of ucMGP deposition around arterial calcification, the circulating fraction of ucMGP is decreased. Here we report on the development of an ucMGP assay and the potential diagnostic utility of monitoring serum ucMGP levels. METHODS AND RESULTS: An ELISA-based assay was developed with which circulating ucMGP can be determined. Serum ucMGP levels were measured in healthy subjects (n = 165) and in four patient populations; patients who underwent angioplasty (n = 30), patients with aortic stenosis (n = 25), hemodialysis patients (n = 52), and calciphylaxis patients (n = 10). All four patient populations had significantly lower ucMGP levels. In angioplasty patients and in those with aortic stenosis, some overlap was observed with the control population. However, in the hemodialysis and calciphylaxis populations, virtually all subjects had ucMGP levels below the normal adult range. CONCLUSION: Serum ucMGP may be used as a biomarker to identify those at risk for developing vascular calcification. This assay may become an important tool in the diagnosis of cardiovascular calcification. 2008 S. Karger AG, Basel.

PMID: 18401181 [PubMed - indexed for MEDLINE]

Related ArticlesUndercarboxylated matrix GLA protein levels are decreased in dialysis patients and related to parameters of calcium-phosphate metabolism and aortic augmentation index. [Blood Purif. 2007] Novel conformation-specific antibodies against matrix gamma-carboxyglutamic acid (Gla) protein: undercarboxylated matrix Gla protein as marker for vascular calcification. [Arterioscler Thromb Vasc Biol. 2005] Serum levels of calcification inhibition proteins and coronary artery calcium score: comparison between transplantation and dialysis. [Am J Nephrol. 2007] ReviewMatrix Gla-protein: the calcification inhibitor in need of vitamin K. [Thromb Haemost. 2008] Review[Calcified coronary artery disease and serum markers] [Clin Calcium. 2007] » See Reviews... | » See All...

1: Calcif Tissue Int. 2008 Sep;83(3):192-201. Epub 2008 Aug 29. Links
Relationship between arterial calcification and bone loss in a new combined model rat by ovariectomy and vitamin D(3) plus nicotine.Park JH, Omi N, Iemitsu M, Maeda S, Kitajima A, Nosaka T, Ezawa I.
Institute of Health and Sports Sciences, University of Tsukuba, Tsukuba, Ibaraki 305-8574, Japan.

Epidemiological studies have reported an association between arterial calcification and bone loss after menopause. However, the underlying mechanism of the association remains unclear. Therefore, to explore the possible mechanisms of the association, we tried to develop a new combined model rat of ovariectomy (OVX, an animal model of osteoporosis) and vitamin D(3) plus nicotine (VDN rat, an animal model of arterial calcification). We tested them by using sham-operated control rats (SC), OVX control rats (OC), and OVX plus VDN-treated rats (OVN). Dissections were performed twice at 4 (4SC, 4OC, and 4OVN) and 8 (8SC, 8OC, and 8OVN) weeks after treatment. 8OVN showed bone loss and arterial calcification, although 8OC showed only bone loss. Moreover, arterial calcium content was associated with indexes of bone loss at 8 weeks. Thus, the OVN rat is considered a good model to examine the relationship of the two disorders after menopause. Additionally, the arterial endothelin-1 (ET-1, a potent regulator of arterial calcification) levels increased in both 4OVN and 8OVN, and the level was associated with arterial calcium content at 8 weeks. Furthermore, the arterial endothelial nitric oxide synthase (eNOS) protein, which is an enzyme that produces nitric oxide (an antiatherosclerotic substance), was significantly reduced in only 8OVN. Estrogens affect the alterations of the eNOS and ET-1 proteins. Therefore, we suggest that impairment of the ET-1- and NO-producing system in arterial tissue during periods of rapid bone loss by estrogen deficiency might be a mechanism of the relationship between the two disorders seen in postmenopausal women.

PMID: 18758843 [PubMed - in process]

1: Am J Physiol Heart Circ Physiol. 2008 Sep;295(3):H931-H938. Epub 2008 Jul 11. Links
Characterization of blood borne microparticles as markers of premature coronary calcification in newly menopausal women.Jayachandran M, Litwiller RD, Owen WG, Heit JA, Behrenbeck T, Mulvagh SL, Araoz PA, Budoff MJ, Harman SM, Miller VM.
Department of Surgery and Physiology and Biomedical Engineering, Mayo Clinic College of Medicine, 200 1st St. SW, Rochester, MN 55905, USA. jaya.m@mayo.edu

While the risk for symptomatic atherosclerotic disease increases after menopause, currently recognized risk factors do not identify ongoing disease processes in low-risk women. This study tested the hypothesis that circulating cell-derived microparticles may reflect disease processes in women defined as low risk by the Framingham risk score. The concentration and phenotype of circulating microparticles were evaluated in a cross-sectional study of apparently healthy menopausal women, screened for enrollment into the Kronos Early Estrogen Prevention Study. Microparticles were evaluated by flow cytometry, and coronary artery calcification (CAC) was scored using 64-slice computed tomography scanners. The procoagulant activity of isolated microparticles was determined with a sensitive fluorescent thrombin generation assay. Chronological age, body mass index, serum lipids, systolic blood pressure (Framingham risk score < 10%, range 1-3%), and high-sensitivity C-reactive protein did not differ significantly among women with low (0 < 35; range, 0.3-32 Agatston units) or high (>50; range, 93-315 Agatston units) CAC compared with women without calcification. The total concentration and percentage of microparticles derived from platelets and endothelial cells were greatest in women with high CAC scores. The thrombin-generating capacity of the isolated microparticles correlated with phosphatidylserine expression, which also was greatest in women with high CAC scores. The percentages of microparticles expressing granulocyte and monocyte markers were not significantly different among groups. Therefore, the characterization of platelet and endothelial microparticles may identify early menopausal women with premature CAC who would not otherwise be identified by the usual risk factor analysis.

PMID: 18621859 [PubMed - indexed for MEDLINE]

1: Cell Tissue Res. 2009 Jan;335(1):143-51. Epub 2008 Nov 7. Links
Endothelial microparticles in diseases.Chironi GN, Boulanger CM, Simon A, Dignat-George F, Freyssinet JM, Tedgui A.
AP-HP, Hôpital Européen Georges Pompidou, Centre de Médecine Préventive Cardiovasculaire and Université René Descartes, Paris, France. gilles.chironi@brs.aphp.fr

Microparticles are submicron vesicles shed from plasma membranes in response to cell activation, injury, and/or apoptosis. The measurement of the phospholipid content (mainly phosphatidylserine; PSer) of microparticles and the detection of proteins specific for the cells from which they are derived has allowed their quantification and characterization. Microparticles of various cellular origin (platelets, leukocytes, endothelial cells) are found in the plasma of healthy subjects, and their amount increases under pathological conditions. Endothelial microparticles (EMP) not only constitute an emerging marker of endothelial dysfunction, but are also considered to play a major biological role in inflammation, vascular injury, angiogenesis, and thrombosis. Although the mechanisms leading to their in vivo formation remain obscure, the release of EMP from cultured cells can be caused in vitro by a number of cytokines and apoptotic stimuli. Recent studies indicate that EMP are able to decrease nitric-oxide-dependent vasodilation, increase arterial stiffness, promote inflammation, and initiate thrombosis at their PSer-rich membrane, which highly co-expresses tissue factor. EMP are known to be elevated in acute coronary syndromes, in severe hypertension with end organ damage, and in thrombotic thrombocytopenic purpura, all conditions associated with endothelial injury and pro-thrombotic state. The release of EMP has also been associated with endothelial dysfunction of patients with multiple sclerosis and lupus anticoagulant. More recent studies have focused on the role of low shear stress leading to endothelial cell apoptosis and subsequent EMP release in end-stage renal disease. Improved knowledge of EMP composition, their biological effects, and the mechanisms leading to their clearance will probably open new therapeutic approaches in the treatment of atherothrombosis.

PMID: 18989704 [PubMed - in process]

1: Neurology. 2001 May 22;56(10):1319-24. Links
Elevated plasma endothelial microparticles in multiple sclerosis.Minagar A, Jy W, Jimenez JJ, Sheremata WA, Mauro LM, Mao WW, Horstman LL, Ahn YS.
Department of Neurology, University of Miami, FL 33136, USA.

OBJECTIVE: To assess endothelial dysfunction in patients with MS and to investigate whether plasma from patients with MS induces endothelial cell dysfunction in vitro. BACKGROUND: Endothelial cell dysfunction may contribute to the pathogenesis of MS. Elevations of soluble adhesion molecules intracellular adhesion molecule, vascular cell adhesion molecule, and platelet-endothelial cell adhesion molecule-1 (CD31) have been reported as markers of blood-brain barrier (BBB) damage in MS, but direct assay of endothelium has been difficult. Endothelial cells release microparticles < approximately 1.5 microm (EMP) during activation or apoptosis. The authors developed a flow cytometric assay of EMP and studied EMP as markers of endothelial damage in MS. METHODS: Platelet-poor plasma (PPP) from 50 patients with MS (30 in exacerbation and 20 in remission) and 48 controls were labeled with fluorescein isothiocyanate (FITC)-conjugated anti-CD31 and anti-CD51 (vitronectin receptor) antibodies, and two classes of EMP (CD31+ and CD51+) were assayed by flow cytometry. For in vitro studies, patients' plasma was added to the microvascular endothelial cell (MVEC) culture and release of CD31+ and CD51+ EMP were measured in the supernatant. RESULTS: Plasma from patients in exacerbation had 2.85-fold elevation of CD31+ EMP as compared with healthy controls, returning to near control value during remission. The CD31+ EMP concentration showed a positive association with gadolinium enhancement in patients with MS. In contrast, CD51+ EMP remained elevated in both exacerbation and remission. This suggests that CD31+ EMP is a marker of acute injury, whereas CD51+ EMP reflects chronic injury of endothelium. MS plasma induced release of both CD31+ and CD51+ EMP from MVEC culture in vitro. CONCLUSION: Endothelial dysfunction is evident during exacerbation of MS, evidenced by shedding of EMP expressing PECAM-1 (CD31). The in vitro data indicate contribution of one or more plasma factors in endothelial dysfunction of MS.

PMID: 11376181 [PubMed - indexed for MEDLINE]

1: Thromb Res. 2008;122(3):411-7. Epub 2008 Jan 30. Links
Effects of the blood coagulation vitamin K as an inhibitor of arterial calcification.Wallin R, Schurgers L, Wajih N.
Department of Internal Medicine, Wake Forest University School of Medicine, Medical Center Boulevard, Winston-Salem, North Carolina 27157, USA. rwallin@wfubmc.edu

INTRODUCTION: The transformation of smooth muscle cells (VSMCs) in the vessel wall to osteoblast like cells is known to precede arterial calcification which may cause bleeding complications. The vitamin K-dependent protein MGP has been identified as an inhibitor of this process by binding BMP-2, a growth factor known to trigger the transformation. In this study, we determined if the vitamin K-dependent Gla region in MGP by itself can inhibit the growth factor activity of BMP-2 and if menaquinone-4 (MK4) regulates gene expression in VSMCs. MATERIALS AND METHODS: A synthetic gamma-carboxyglutamic acid (Gla) containing peptide covering the Gla region in human MGP was used to test its ability to inhibit BMP-2 induced transformation of mouse pro-myoblast C2C12 cells into osteoblasts. MK4 was tested by microarray analysis as a gene regulatory molecule in VSMCs. RESULTS AND CONCLUSIONS: The results show that the Gla - but not the Glu-peptide inhibited the transformation which provide evidence that the Gla region in MGP is directly involved in the BMP-2/MGP interaction and emphasizes the importance of the vitamin K-dependent modification of MGP. From the data obtained from the microarray analysis, we focused on two quantitatively altered cDNAs representing proteins known to be associated with vessel wall calcification. DT-diaphorase of the vitamin K-cycle, showed increased gene expression with a 4.8-fold higher specific activity in MK4 treated cells. Osteoprotegrin gene expression was down regulated and osteoprotegrin protein secretion from the MK4 treated cells was lowered to 1.8-fold. These findings suggest that MK4 acts as an anti-calcification component in the vessel wall.

PMID: 18234293 [PubMed - indexed for MEDLINE]

1: J Atheroscler Thromb. 2007 Dec;14(6):317-24. Epub 2007 Dec 17. Links
Treatment with vitamin k(2) combined with bisphosphonates synergistically inhibits calcification in cultured smooth muscle cells.Saito E, Wachi H, Sato F, Sugitani H, Seyama Y.
Department of Clinical Chemistry, Hoshi University School of Pharmacy and Pharmaceutical Sciences, Japan.

AIM: Vascular calcification is a common feature in patients with advanced atherosclerosis, postmenopausal women and patients with renal failure, which results in reduced elasticity of arteries. Pamidronate, a bisphosphonate, is used as a therapeutic agent for anti-osteoporosity, although there are adverse side effects, such as renal damage and aortic inflamed plaque rupture. In the present study, we demonstrated the effects of vitamin K(2) alone or in combination with pamidronate in an arterial calcification model induced using inorganic phosphate in cultured bovine aortic smooth muscle cells (BASMCs). METHODS: Calcification was induced by the addition of Pi (3 mM) in BASMCs. Calcium deposition was determined by Calcium C-test Wako and von Kossa staining. mRNA expression was assessed by semi-quantitative reverse transcription-polymerase chain reaction. RESULTS: Calcium deposition assay and von Kossa staining showed that calcification could be inhibited in a dose-dependent manner by treatment with vitamin K(2) alone, and that its inhibitory effect was enhanced when combined with pamidronate. It was found that the expression of tropoelastin mRNA was synergistically enhanced by combined treatment with vitamin K(2) and pamidronate, and the expression matrix Gla protein mRNA and osteopontin mRNA expression were also enhanced and suppressed, respectively, by treatment with vitamin K(2) or pamidronate. Moreover, our data showed that the suppression of TE expression by siRNA significantly increased Pi-induced vascular calcification. CONCLUSION: Taken together, our study suggests that vitamin K(2) in combination with pamidronate synergistically inhibits arterial calcification via the increased expression of tropoelastin, which would be a useful marker for developing effective therapeutic or prophylactic agents for arterial calcification.

PMID: 18174662 [PubMed - indexed for MEDLINE]

Posted: Sat Dec 06, 2008 11:36 pm Post subject:
I haven't seen it mentioned here, but recently I have been reading a lot on Vitamin K2 (in relation to Vit D3).

From memory, its attributed to:
1. Improve Vascular Health
2. Improve bone density / calcium absorption.
3. Reduce the chance of developing Gout (ie crystals in joints) during times of high Uric Acid (without reducing uric acid).

I haven't read anything glowing in regards to MS in particular, but I have yet to read anything negative about it. The above positives all sound like things I would like to benefit from, so will attempt to get my hands on it.

jimmylegs wrote:cheer you found a natto supp that didn't have the k2 removed?

Low-Dose Vitamin K2
45 mcg, 90 softgels
Item Catalog Number: 01225
An abundance of human clinical data reveals that vitamin K plays a critical role in maintaining healthy bone density by facilitating the transport of calcium from the bloodstream into the bone.3,5,6,13,19 Scientists are getting to understand that vitamin K is also required by calcium-regulating proteins in the arteries. Matrix Glaprotein (MGP) is a vitamin K-dependent protein, and must be carboxylated to function properly; poor vitamin K status results in synthesis of uncarboxylated MGP (ucMGP). Since MGP is a potent local inhibitor of arterial calcification, MGP is important in relation to the health of the entire cardiovascular system. Without adequate vitamin K, calcium in the blood can bind to the arterial wall resulting in calcification. As people age, even a subclinical vitamin K deficiency can pose risks to the vascular system.

Vitamin K2 (menaquinones) is found in meat, eggs, and dairy products and also made by bacteria in the human gut, which provides a certain amount of the human vitamin K requirement. Human studies show that vitamin K2 is absorbed up to ten times more than K1. Vitamin K2 remains biologically active in the body far longer than K1. For instance, K1 is rapidly cleared by the liver within eight hours, whereas measurable levels of K2 have been detected 72 hours after ingestion.2

The Rotterdam Heart Study, a large-scale, well-controlled clinical trial that tracked 4,800 participants for seven years, revealed that participants who ingested the greatest quantities of vitamin K2 in their diet experienced a better cardiovascular condition than people who ingested the least. High intakes of vitamin K2 also corresponded to less calcium deposition in the aorta, whereas participants who ingested less K2 were more likely to show moderate or severe calcification. Animal studies suggest vitamin K intake not only blocks the progress of further calcium accumulation but also induces 37% regression of preformed arterial calcification.7,8

Life Extension's Low Dose Vitamin K2 contains the menaquinone-7 form of vitamin K2, which is not metabolized quickly by the liver, thereby making it available to provide a more consistent supply of vitamin K to the body.

1: J Interv Card Electrophysiol. 2008 Sep;22(3):173-5. Epub 2008 May 28. Links
Pulmonary vein calcification by EBCT in patients with drug refractory nonvalular atrial fibrillation.Adams J, Natale A, Elayi CS, Di Biase L, Martin DO, Beheiry S, Hao S, Hongo R, Ching CK.
Sutter Pacific Heart Centers, San Francisco, CA, USA.

INTRODUCTION: Pulmonary veins in patients with atrial fibrillation (AF) have been shown to be highly arrhythmogenic. Calcification in these veins may play an adjunctive role in the pathogenesis of AF. METHODS AND RESULTS: A case control study was performed in patients with drug refractory nonvalvular AF whose preablation computed tomography chest scans demonstrated pulmonary vein (PV) calcification. Eight out of 48 patients with PV calcification were compared to 50 patients without AF who underwent electron beam computed tomography coronary artery calcium scores. These patients were matched for age, gender, coronary artery calcium scores, and the presence of PV calcification. The mean age of the combined group was 57 +/- 9 years and 60% were men. The mean total PV calcium score was significantly higher at 199 +/- 112 in patients with AF compared to 106 +/- 52 in controls (p = 0.018). Men had significantly higher total PV calcium score than women in both groups. CONCLUSION: Total PV calcium score was significantly higher in patients with atrial fibrillation. Increased PV calcification may play an adjunctive role in the pathogenesis in initiating and maintaining AF.

PMID: 18506608 [PubMed - indexed for MEDLINE]

1: ScientificWorldJournal. 2006 Jun 30;6:734-6. Links
Prenatal calcification of the inferior vena cava and renal veins in a normal neonate.Ranch D, Aigbe MO, Gorospe EC.
1Department of Pediatrics, University of Nevada School of Medicine, Las Vegas, USA. dranch999@yahoo.com

Prenatal calcification of the inferior vena cava (IVC) and renal veins is a rare condition with unclear etiology and prognosis. It occurs with renal vein thrombosis in utero and is associated with congenital anomalies and abnormal prenatal hemodynamic status. We report a rare case of prenatal IVC and renal vein calcification in a normal neonate without any history of compromised prenatal or perinatal condition, or significant deterioration of kidney function.

PMID: 16816883 [PubMed - indexed for MEDLINE]

1: Med Hypotheses. 2007;68(5):1026-34. Epub 2006 Dec 4. Links
Vitamin D toxicity redefined: vitamin K and the molecular mechanism.Masterjohn C.
Weston A. Price Foundation, 4200 Wisconsin Ave., NW, Washington, DC 20016, United States. ChrisMasterjohn@gmail.com

The dose of vitamin D that some researchers recommend as optimally therapeutic exceeds that officially recognized as safe by a factor of two; it is therefore important to determine the precise mechanism by which excessive doses of vitamin D exert toxicity so that physicians and other health care practitioners may understand how to use optimally therapeutic doses of this vitamin without the risk of adverse effects. Although the toxicity of vitamin D has conventionally been attributed to its induction of hypercalcemia, animal studies show that the toxic endpoints observed in response to hypervitaminosis D such as anorexia, lethargy, growth retardation, bone resorption, soft tissue calcification, and death can be dissociated from the hypercalcemia that usually accompanies them, demanding that an alternative explanation for the mechanism of vitamin D toxicity be developed. The hypothesis presented in this paper proposes the novel understanding that vitamin D exerts toxicity by inducing a deficiency of vitamin K. According to this model, vitamin D increases the expression of proteins whose activation depends on vitamin K-mediated carboxylation; as the demand for carboxylation increases, the pool of vitamin K is depleted. Since vitamin K is essential to the nervous system and plays important roles in protecting against bone loss and calcification of the peripheral soft tissues, its deficiency results in the symptoms associated with hypervitaminosis D. This hypothesis is circumstantially supported by the observation that animals deficient in vitamin K or vitamin K-dependent proteins exhibit remarkable similarities to animals fed toxic doses of vitamin D, and the observation that vitamin D and the vitamin K-inhibitor Warfarin have similar toxicity profiles and exert toxicity synergistically when combined. The hypothesis further proposes that vitamin A protects against the toxicity of vitamin D by decreasing the expression of vitamin K-dependent proteins and thereby exerting a vitamin K-sparing effect. If animal experiments can confirm this hypothesis, the models by which the maximum safe dose is determined would need to be revised. Physicians and other health care practitioners would be able to treat patients with doses of vitamin D that possess greater therapeutic value than those currently being used while avoiding the risk of adverse effects by administering vitamin D together with vitamins A and K.

PMID: 17145139 [PubMed - indexed for MEDLINE]