Multifunctional roles for serum protein fetuin-a in inhibition of human vascular smooth muscle cell calcification.
Vascular calcification predicts an increased risk for cardiovascular events/mortality in atherosclerosis, diabetes, and ESRD. Serum concentrations of alpha(2)-Heremens-Schmid glycoprotein, commonly referred to as fetuin-A, are reduced in ESRD, a condition associated with an elevated circulating calcium x phosphate product. Mice that lack fetuin-A exhibit extensive soft tissue calcification, which is accelerated on a mineral-rich diet, suggesting that fetuin-A acts to inhibit calcification systemically. Western blot and immunohistochemistry demonstrated that serum-derived fetuin-A co-localized with calcified human vascular smooth muscle cells (VSMC) in vitro and in calcified arteries in vivo. Fetuin-A inhibited in vitro VSMC calcification, induced by elevated concentrations of extracellular mineral ions, in a concentration-dependent manner. This was achieved in part through inhibition of apoptosis and caspase cleavage. Confocal microscopy and electron microscopy-immunogold demonstrated that fetuin-A was internalized by VSMC and concentrated in intracellular vesicles. Subsequently, fetuin-A was secreted via vesicle release from apoptotic and viable VSMC. Vesicles have previously been identified as the nidus for mineral nucleation. The presence of fetuin-A in vesicles abrogated their ability to nucleate basic calcium phosphate. In addition, fetuin-A enhanced phagocytosis of vesicles by VSMC. These observations provide evidence that the uptake of the serum protein fetuin-A by VSMC is a key event in the inhibition of vesicle-mediated VSMC calcification. Strategies aimed at maintaining normal circulating levels of fetuin-A may prove beneficial in patients with ESRD.
Reynolds
Joanne L
JL
Division of Cardiovascular Medicine, Level 6, ACCI, Box 110, Addenbrooke's Hospital, Hills Road, Cambridge CB2 2QQ, UK.
Skepper
Jeremy N
JN
McNair
Rosamund
R
Kasama
Takeshi
T
Gupta
Kunal
K
Weissberg
Peter L
PL
Jahnen-Dechent
Willi
W
Shanahan
Catherine M
CM
D001798:Blood Proteins / Q000502:physiology*; D002114:Calcinosis / Q000517:prevention & control; D002478:Cells, Cultured; D006801:Humans; D009131:Muscle, Smooth, Vascular / Q000166:cytology* / Q000473:pathology; D060749:alpha-2-HS-Glycoprotein
C556354:AHSG protein, human; C556357:Ahsg protein, mouse; D001798:Blood Proteins; D060749:alpha-2-HS-Glycoprotein