Identification of differentially expressed genes in human varicose veins: involvement of matrix gla protein in extracellular matrix remodeling.
This study was designed to identify the global pattern of differentially expressed genes in human varicose veins. Using suppressive subtractive hybridization, we identified overexpression of genes known to be associated with extracellular matrix remodeling, including collagen III, tissue inhibitor of metalloproteinases I, dermatopontin, matrix Gla protein (MGP) and tenascin C. Real-time polymerase chain reaction analysis confirmed the differential expression of these genes. The overexpression of MGP transcript was associated with increased MGP level in varicose veins, in particular the undercarboxylated form of the protein. Smooth muscle cells from varicose veins showed increased proliferation rate and enhanced matrix mineralization. This observation correlated with the presence of ectopic mineralization areas in the varicose vein walls. The use of warfarin, to inhibit MGP activity, or siRNA targeting MGP transcript induced a reduction in the exacerbated proliferation of varicose vein smooth muscle cells. Our results suggest that high expression of MGP in varicose veins may contribute to venous wall remodeling by affecting proliferation and mineralization processes probably through impaired carboxylation of MGP. In addition, suppressive subtractive hybridization results also produce a profile of differentially expressed genes in varicose veins, in particular extracellular matrix components. Further study of these genes will provide insights into their specific roles in the etiology of venous disease.
Cario-Toumaniantz
Chrystelle
C
INSERM, U533, Université de Nantes, Faculté des Sciences et Techniques, l'Institut du Thorax, Nantes, France. ccario@nantes.inserm.fr
Boularan
Cédric
C
Schurgers
Leon J
LJ
Heymann
Marie-Françoise
MF
Le Cunff
Martine
M
Léger
Jean
J
Loirand
Gervaise
G
Pacaud
Pierre
P
D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D002114:Calcinosis / Q000235:genetics* / Q000378:metabolism / Q000473:pathology; D002135:Calcium-Binding Proteins / Q000037:antagonists & inhibitors / Q000235:genetics* / Q000378:metabolism; D016022:Case-Control Studies; D049109:Cell Proliferation; D002478:Cells, Cultured; D004305:Dose-Response Relationship, Drug; D005109:Extracellular Matrix / Q000378:metabolism*; D016326:Extracellular Matrix Proteins / Q000037:antagonists & inhibitors / Q000235:genetics* / Q000378:metabolism; D020869:Gene Expression Profiling / Q000379:methods; D005786:Gene Expression Regulation; D005994:Glycerophosphates / Q000378:metabolism; D006801:Humans; D008297:Male; D008875:Middle Aged; D009131:Muscle, Smooth, Vascular / Q000187:drug effects / Q000378:metabolism* / Q000473:pathology; D020411:Oligonucleotide Array Sequence Analysis; D011499:Protein Processing, Post-Translational; D034622:RNA Interference; D012333:RNA, Messenger / Q000378:metabolism; D034741:RNA, Small Interfering / Q000378:metabolism; D015203:Reproducibility of Results; D020133:Reverse Transcriptase Polymerase Chain Reaction; D012501:Saphenous Vein / Q000378:metabolism; D015854:Up-Regulation; D014648:Varicose Veins / Q000235:genetics* / Q000378:metabolism / Q000473:pathology; D014859:Warfarin / Q000494:pharmacology; D000097568:Matrix Gla Protein
D002135:Calcium-Binding Proteins; D016326:Extracellular Matrix Proteins; D005994:Glycerophosphates; D012333:RNA, Messenger; D034741:RNA, Small Interfering; D014859:Warfarin; D000097568:Matrix Gla Protein