PDGF-CC induces tissue factor expression: role of PDGF receptor alpha/beta.
Tissue factor (TF) is the principal trigger of the coagulation cascade and involved in arterial thrombus formation. Platelet-derived growth factor CC (PDGF-CC) is a recently discovered member of the PDGF family released upon platelet activation. This study assesses the impact of PDGF-CC on TF expression in human cells. PDGF-CC concentration-dependently induced TF expression by 2.5-fold in THP-1 cells, by 2.0-fold in human peripheral blood monocytes, by 1.4-fold in vascular smooth muscle cells, and by 2.6-fold in microvascular endothelial cells, but did not affect TF expression in aortic endothelial cells. A similar pattern was observed with PDGF-BB. In contrast, PDGF-AA did not alter TF expression in THP-1 cells. TF whole cell activity was induced following stimulation with PDGF-BB and PDGF-CC in THP-1 cells. Real-time polymerase chain reaction revealed that PDGF-CC induced TF mRNA. PDGF-CC transiently activated p42/44 MAP kinase [extracellular signal-regulated kinase (ERK)], while phosphorylation of the MAP kinases c-Jun NH(2)-terminal kinase (JNK) and p38 remained unaffected. PD98059, a specific inhibitor of ERK phosphorylation, but not the p38 inhibitor SB203580 or the JNK inhibitor SP600125 prevented PDGF-CC induced TF expression in a concentration-dependent manner. The effect of PDGF-CC was antagonized by both PDGF receptor alpha and PDGF receptor beta neutralizing antibodies; in contrast, PDGF-BB was only inhibited by PDGF receptor beta blocking antibody. PDGF receptor alpha and PDGF receptor beta inhibition prevented PDGF-CC-induced ERK phosphorylation. PDGF-CC induces TF expression via activation of alpha/beta receptor heterodimers and an ERK-dependent signal transduction pathway.
Cardiovascular Research, Physiology Institute, University of Zurich, Zurich, Switzerland.
Cathérine
C
Gebhard
Alexander
A
Akhmedov
Pavani
P
Mocharla
Jonas
J
Angstenberger
Saba
S
Sahbai
Giovanni G
GG
Camici
Thomas F
TF
Lüscher
Felix C
FC
Tanner
D000077214:Becaplermin; D017871:Calcium-Calmodulin-Dependent Protein Kinases / Q000037:antagonists & inhibitors; D002478:Cells, Cultured; D004305:Dose-Response Relationship, Drug; D004730:Endothelium, Vascular / Q000166:cytology / Q000187:drug effects / Q000378:metabolism*; D048049:Extracellular Signal-Regulated MAP Kinases / Q000378:metabolism; D005419:Flavonoids / Q000494:pharmacology; D006801:Humans; D007963:Leukocytes, Mononuclear / Q000166:cytology / Q000187:drug effects / Q000378:metabolism*; D008222:Lymphokines / Q000494:pharmacology*; D019950:Mitogen-Activated Protein Kinase 1 / Q000378:metabolism; D048052:Mitogen-Activated Protein Kinase 3 / Q000378:metabolism; D009131:Muscle, Smooth, Vascular / Q000166:cytology / Q000187:drug effects / Q000378:metabolism*; D010982:Platelet-Derived Growth Factor / Q000494:pharmacology*; D020574:Proto-Oncogene Proteins c-sis; D012333:RNA, Messenger / Q000378:metabolism; D020796:Receptor, Platelet-Derived Growth Factor alpha / Q000502:physiology*; D020797:Receptor, Platelet-Derived Growth Factor beta / Q000502:physiology*; D013925:Thromboplastin / Q000378:metabolism*
D005419:Flavonoids; D008222:Lymphokines; D010982:Platelet-Derived Growth Factor; D020574:Proto-Oncogene Proteins c-sis; D012333:RNA, Messenger; C411423:platelet-derived growth factor C; D000077214:Becaplermin; D013925:Thromboplastin; D020796:Receptor, Platelet-Derived Growth Factor alpha; D020797:Receptor, Platelet-Derived Growth Factor beta; D017871:Calcium-Calmodulin-Dependent Protein Kinases; D048049:Extracellular Signal-Regulated MAP Kinases; D019950:Mitogen-Activated Protein Kinase 1; D048052:Mitogen-Activated Protein Kinase 3; C093973:2-(2-amino-3-methoxyphenyl)-4H-1-benzopyran-4-one