Vitamin K and atherosclerosis

Background information can be found in Section
4.5.8.
The mRNA of matrix Gla protein (MGP) is expressed
by a wide variety of soft tissues, as well as in
developing bone (Fraser & Price, 1988). However, the
protein itself has been found only in bone and calcifi
ed cartilage (Price et al., 2000). This observation
suggests that the protein may accumulate at sites of
calcifi cation owing to its strong binding affi nity to
hydroxyapatite. Indeed, MGP, synthesized in the arterial
intima by macrophages and to a lesser extent by
vascular smooth muscle cells, accumulates in calcifi ed
atherosclerotic plaques. MGP is also synthesized by
vascular smooth muscle cells directly abutting calcifi
ed regions in the arterial media (Shanahan et al.,
2000).
Solid evidence confi rming that MGP is a potent
inhibitor of calcifi cation in vivo comes from mice
that lack MGP (Luo et al., 1997). Targeted deletion
of the MGP gene causes rapid calcifi cation of the
elastic lamellae in the tunica media of the arteries,
but not of the arterioles, capillaries or veins. The entire
media is replaced by chondrocytes, producing a
typical cartilage that starts to progressively calcify at
birth. By 3 to 6 weeks of age, calcifi cation is so extensive
that the arteries become rigid tubes and, within
8 weeks of age, death occurs due to rupture of the
thoracic or abdominal aorta. There is also inappropriate
calcifi cation of proliferating chondrocytes at
the epiphyseal plate of growing long bones, resulting
in stunted bone growth and osteopenia. The vascular
phenotype of the MGP-defi cient mouse suggests that
MGP is an essential inhibitor of arterial calcifi cation.
Furthermore, it indicates that vascular calcifi cation
occurs spontaneously if not actively inhibited. In
humans, mutations in the MGP gene are responsible
for Keutel syndrome, a rare inherited disease characterized
by multiple peripheral pulmonary stenoses,
neural hearing loss, short terminal phalanges, midfacial
hypoplasia, and abnormal calcifi cation of the
cartilage of the auricles, nose, larynx, trachea and ribs
(Munroe et al., 1999).
Contrary to expectations, Shanahan et al. (1994)
found that MGP mRNA is up-regulated in association
with vascular calcifi cation. However, this does
not necessarily mean that the protein product is
functional: function is crucially dependent on vitamin
K-dependent post-translational conversion of
Glu residues to Gla residues. Although γ-carboxylase
activity has been demonstrated in the vessel wall (de
Boer-van den Berg et al., 1986), advancing age and
environmental factors such as diet and medication
may lead to reduced levels of functional MGP. Jie et
al. (1995) reported that post-menopausal women
with calcifi ed atherosclerotic lesions had higher
levels of undercarboxylated osteocalcin and a lower
dietary vitamin K intake than women without calcifi
cations. This study demonstrated that aortic
calcifi cation is associated with a reduced vitamin K
status. Furthermore, the presence of atherosclerotic
calcifi cations was associated with a lower bone mass
(Jie et al., 1996). On the basis that MGP is produced
by the vessel wall as a defence mechanism against
calcifi cation, an insuffi ciency of vitamin K will lead
to the production of nonfunctional MGP, and hence
inappropriate calcifi cation.
Another Gla protein has been isolated from calcifi
ed human atherosclerotic plaques and partly characterized
(Gijsbers et al., 1990). This protein, named
plaque Gla protein (PGP), has a mass of 23 kDa,
268 Vitamins: their role in the human body
contains fi ve Gla residues per molecule, and is structurally
dissimilar from any of the known Gla proteins.
In vitro, PGP is extremely potent in inhibiting the
precipitation of various calcium salts, but its role in
vivo has yet to be demonstrated.
10.5.7 Possible role of vitamin K in the
nervous system
A more recently discovered Gla protein encoded by
a growth arrest-specifi c gene and known as Gas6 has
a wide tissue distribution, including the nervous system.
Gas6 is a ligand for a class of tyrosine kinase receptors
and as such is involved in cell cycle regulation
and cell–cell adhesion. In the nervous system, Gas6 is
a growth factor for Schwann cells and is implicated in
neuronal survival (Tsaioun, 1999).