Retroviral overexpression of decorin differentially affects the response of arterial smooth muscle cells to growth factors.
Decorin is a member of the family of small leucine-rich proteoglycans that are present in blood vessels and synthesized by arterial smooth muscle cells (ASMCs). This proteoglycan accumulates in topographically defined regions of atherosclerotic lesions and may play a role in the development of this disease. However, little is known about whether decorin has specific effects on the cellular events that contribute to atherosclerotic lesion formation. In the present study, rat ASMCs were transduced with a retroviral vector (LDSN) that carries the bovine decorin gene. Compared with vector control cells (LXSN), these cells constitutively overexpress decorin, as verified by Northern and Western analysis and by metabolic labeling. Experiments were performed to examine the responsiveness of decorin-overexpressing rat ASMCs to platelet-derived growth factor (PDGF) and transforming growth factor-beta1 (TGF-beta1), 2 growth factors that affect cell proliferation and extracellular matrix production in atherosclerosis. Decorin-overexpressing cells had decreased [(3)H]thymidine incorporation into DNA and increased the levels of the cyclin-dependent kinase inhibitors p21 and p27 in the first 24 hours of response to serum and PDGF-BB. However, these effects of decorin were not apparent at 48 or 72 hours after plating and did not result in reduced growth of decorin-overexpressing cells in response to serum and PDGF-BB. In contrast, the growth response of decorin-overexpressing ASMCs to TGF-beta1, as well as the expression of TGF-beta1-responsive genes, such as plasminogen activator inhibitor-1 and versican (an extracellular matrix proteoglycan), was diminished. These results indicate that decorin selectively inhibits the responsiveness of rat ASMCs to TGF-beta1 and suggests that the induction of constitutive decorin overexpression by ASMCs in vivo may have therapeutic value in the inhibition of TGF-beta1-mediated effects on the development of atherosclerotic lesions.
Fischer
J W
JW
Department of Pharmacology, Christian Albrechts University, Kiel, Germany.
Kinsella
M G
MG
Levkau
B
B
Clowes
A W
AW
Wight
T N
TN
D000818:Animals; D001158:Arteries / Q000166:cytology / Q000187:drug effects / Q000378:metabolism; D018797:Cell Cycle Proteins; D002455:Cell Division / Q000187:drug effects; D011508:Chondroitin Sulfate Proteoglycans / Q000096:biosynthesis / Q000235:genetics; D050759:Cyclin-Dependent Kinase Inhibitor p21; D050760:Cyclin-Dependent Kinase Inhibitor p27; D016213:Cyclins / Q000378:metabolism; D004247:DNA / Q000096:biosynthesis; D058575:Decorin; D016326:Extracellular Matrix Proteins; D037181:Lectins, C-Type; D008869:Microtubule-Associated Proteins / Q000378:metabolism; D009131:Muscle, Smooth, Vascular / Q000166:cytology / Q000187:drug effects / Q000378:metabolism*; D017395:Plasminogen Activator Inhibitor 1 / Q000096:biosynthesis / Q000235:genetics; D010982:Platelet-Derived Growth Factor / Q000494:pharmacology; D011509:Proteoglycans / Q000096:biosynthesis / Q000235:genetics / Q000502:physiology*; D012333:RNA, Messenger / Q000096:biosynthesis; D051381:Rats; D011916:Rats, Inbred F344; D012190:Retroviridae / Q000235:genetics; D014161:Transduction, Genetic; D016212:Transforming Growth Factor beta / Q000494:pharmacology*; D053773:Transforming Growth Factor beta1; D025521:Tumor Suppressor Proteins; D053675:Versicans
C493958:Cdkn1a protein, rat; C493962:Cdkn1b protein, rat; D018797:Cell Cycle Proteins; D011508:Chondroitin Sulfate Proteoglycans; D050759:Cyclin-Dependent Kinase Inhibitor p21; D016213:Cyclins; C546880:Dcn protein, rat; D058575:Decorin; D016326:Extracellular Matrix Proteins; D037181:Lectins, C-Type; D008869:Microtubule-Associated Proteins; D017395:Plasminogen Activator Inhibitor 1; D010982:Platelet-Derived Growth Factor; D011509:Proteoglycans; D012333:RNA, Messenger; C508962:Tgfb1 protein, rat; D016212:Transforming Growth Factor beta; D053773:Transforming Growth Factor beta1; D025521:Tumor Suppressor Proteins; C508324:Vcan protein, rat; D053675:Versicans; D050760:Cyclin-Dependent Kinase Inhibitor p27; D004247:DNA