Thrombospondin-4 and its variants: expression and differential effects on endothelial cells.
BACKGROUND
In a recent large-scale genetic association study, a single nucleotide polymorphism in the thrombospondin-4 (TSP-4) gene, resulting in a proline-for-alanine substitution at position 387, was associated with a significantly increased risk for premature atherosclerosis. TSP-4 had not previously been implicated in vascular pathology, and very little information is available on its expression and functions.


RESULTS
The goal of this study was to assess TSP-4 expression in vessel wall and to identify differences in functions of TSP-4 variants that could account for the proatherogenic effects of the (P387)TSP-4 variant. TSP-4 expression was demonstrated in human endothelial cells (ECs) and vascular smooth muscle cells from brain blood vessels and coronary arteries. (P387)TSP-4 and its fragment (residues 326 to 722), but not the A(387) forms, suppressed EC adhesion and proliferation. The (P387)TSP-4 was more active in inducing the phosphorylation of focal adhesion kinase, consistent with inhibition of proliferation. Both variant fragments increased the proliferation of human aortic smooth muscle cells.


CONCLUSIONS
TSP-4 is expressed by vascular cells and influences the vessel wall by modulating the proliferation of ECs and smooth muscle cells. The A387P substitution is a "gain-of-function" mutation, favoring a form of TSP-4 that interferes with EC adhesion and proliferation and may thereby be proatherogenic.
Stenina
Olga I
OI
Department of Molecular Cardiology, Cleveland Clinic Foundation, Cleveland, Ohio, USA.
Desai
Shailesh Y
SY
Krukovets
Irene
I
Kight
Kelly
K
Janigro
Damir
D
Topol
Eric J
EJ
Plow
Edward F
EF
D001161:Arteriosclerosis / Q000235:genetics; D002448:Cell Adhesion / Q000187:drug effects / Q000502:physiology; D002455:Cell Division / Q000187:drug effects / Q000502:physiology; D002478:Cells, Cultured; D004730:Endothelium, Vascular / Q000166:cytology / Q000187:drug effects / Q000378:metabolism*; D051417:Focal Adhesion Kinase 1; D051416:Focal Adhesion Protein-Tyrosine Kinases; D015870:Gene Expression; D006801:Humans; D007668:Kidney / Q000166:cytology / Q000378:metabolism; D020768:Middle Cerebral Artery / Q000166:cytology; D009131:Muscle, Smooth, Vascular / Q000166:cytology / Q000187:drug effects / Q000378:metabolism; D009154:Mutation; D010446:Peptide Fragments / Q000737:chemistry / Q000494:pharmacology; D010766:Phosphorylation / Q000187:drug effects; D020641:Polymorphism, Single Nucleotide; D011505:Protein-Tyrosine Kinases / Q000378:metabolism; D012333:RNA, Messenger / Q000378:metabolism; D012307:Risk Factors; D019699:Thrombospondins / Q000096:biosynthesis* / Q000235:genetics / Q000494:pharmacology; D014162:Transfection
D010446:Peptide Fragments; D012333:RNA, Messenger; D019699:Thrombospondins; C101864:thrombospondin 4; D011505:Protein-Tyrosine Kinases; D051417:Focal Adhesion Kinase 1; D051416:Focal Adhesion Protein-Tyrosine Kinases; C496050:PTK2 protein, human