Universiteit Maastricht

Gla proteins

 

In the arterial vessel wall the functions of Gla-proteins are associated with: local inhibition of thrombosis (protein S), inhibition of mineralization (MGP), and stimulation of normal cell growth and prevention of apoptosis in growth arrested cells (Gas6). In the circulation protein S is known to inhibit blood coagulation and thrombus formation by acting as a cofactor for activated protein C; there are no arguments suggesting that the function of the vascular synthesised protein S would be different. As was discussed above, MGP-deficient mice were born to term but died before the 8th week of life due to massive arterial calcification and rupture of the thoracic or abdominal aorta. These experiments established that MGP is a strong inhibitor of soft tissue calcification including cartilage and vessel wall. Excessive aorta mineralization was also observed in rats after 4-6 weeks of treatment with vitamin K-antagonists, showing that the Gla-residues in MGP are essential for its function.


Figure: Medial vascular calcification in rats induced by the vitamin K antagonist warfarin.

Gla-proteins have been extracted from human atheromatous plaques and although they were only partially characterized, the poor solubility of the human vascular Gla-proteins suggests that the major fraction may be similar to MGP. The function of Gas6 (which stands for: growth arrest specific gene 6 protein) has been investigated only in cell culture systems thus far. In response to conditions leading to cell death, for instance during serum starvation, cells are induced to produce growth arrest specific proteins. Most of these proteins promote cell death (apoptosis), but Gas6 is an exception in this respect: it was shown to prevent serum starvation-induced death of fibroblasts and smooth muscle cells, and also may act as a growth-potentiating factor which acts synergistically with other known growth factors in these cells. Gla-residues were shown to be essential for its functions in cell culture. These data suggest that in humans Gas6 may play a key role in preventing the degeneration of atherosclerotic vessels. The recent observation that Gas6 is produced in both spinal motor neurons and large neurons of the dorsal root ganglia, and that Gas6 is a potent stimulator of human Schwann cell growth suggests that this protein is involved in growth regulation in other tissues as well, but this needs further confirmation.

Figure adapted from Shanahan CM. Vascular calcification. Curr Opin Nephrol Hypertens 14:361-367.

Recommended literature

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  • Schinke T, McKee MD, Karsenty G. Extracellular matrix calcification: where is the action?. Nat Genet. 1999;21:150-151.
  • 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.
  • Nakano T, Kawamoto K, Kishino J, Nomura K, Higashino K, Arita H. Requirement of gamma-carboxyglutamic acid residues for the biological activity of Gas6: contribution of endogenous Gas6 to the proliferation of vascular smooth muscle cells. Biochem J. 1997;323:387-392.
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  • Luo G, Ducy P, McKee MD, Pinero GJ, Loyer E, Behringer RR, Karsenty G. Spontaneous calcification of arteries and cartilage in mice lacking matrix GLA protein.Nature.1997;385:78-81.