Carvedilol inhibits platelet-derived growth factor-induced extracellular matrix synthesis by inhibiting cellular reactive oxygen species and mitogen-activated protein kinase activation.
BACKGROUND
Vascular smooth muscle cell (VSMC) proliferation, migration, and extracellular matrix (ECM) synthesis are major pathologic features of chronic allograft vasculopathy. Carvedilol, an anti-hypertensive agent, might be an effective agent for preventing the development and progression of chronic allograft vasculopathy, since it can inhibit VSMC proliferation and migration. The present study was designed to examine the effect of carvedilol on platelet-derived growth factor (PDGF)-induced ECM synthesis in rat VSMCs. Furthermore, we evaluated whether carvedilol inhibits PDGF-induced cellular reactive oxygen species (ROS) and the activation of mitogen-activated protein kinase (MAPK).


METHODS
Primary cultured rat VSMCs were stimulated with PDGF-BB (10 ng/ml) in the presence or absence of carvedilol, and the effects of carvedilol were compared with those of ROS or MAPK inhibitors. Fibronectin secretion, proliferating cell nuclear antigen (PCNA) expression, and each MAPK activation were determined by Western blot analysis, total collagen synthesis by [3H]-proline incorporation, and cellular ROS by flow cytometry.


RESULTS
PDGF significantly increased PCNA expression, fibronectin secretion, total collagen synthesis, cellular ROS, and MAPK activation in rat VSMCs. Carvedilol at doses that inhibited PDGF-induced cell proliferation, inhibited ECM synthesis, cellular ROS, or subsequent MAPK activation. Structurally different anti-oxidants and extracellular signal-regulated protein kinase or p38 MAPK inhibitor effectively inhibited PDGF-induced fibronectin secretion and total collagen synthesis.


CONCLUSIONS
These results suggest that carvedilol inhibits PDGF-induced VSMC proliferation and matrix protein synthesis by inhibiting cellular ROS and the subsequent activation of MAPK. Thus the targeted inhibition of cellular ROS and MAPK might provide an effective therapeutic strategy to treat chronic allograft vasculopathy.
Park
Jehyun
J
The Research Institute for Transplantation and BK-21 for Medical Science, Yonsei University College of Medicine, Seoul, Korea.
Ha
Hunjoo
H
Kim
Myoung Soo
MS
Ahn
Hyung Joon
HJ
Huh
Kyu Ha
KH
Kim
Yu Seun
YS
D000818:Animals; D000959:Antihypertensive Agents / Q000494:pharmacology*; D015153:Blotting, Western; D002227:Carbazoles / Q000494:pharmacology*; D000077261:Carvedilol; D049109:Cell Proliferation / Q000187:drug effects; D002478:Cells, Cultured; D005109:Extracellular Matrix / Q000187:drug effects*; D005434:Flow Cytometry; D020928:Mitogen-Activated Protein Kinases / Q000378:metabolism*; D009131:Muscle, Smooth, Vascular / Q000166:cytology*; D010982:Platelet-Derived Growth Factor / Q000502:physiology; D011412:Propanolamines / Q000494:pharmacology*; D051381:Rats; D017207:Rats, Sprague-Dawley; D017382:Reactive Oxygen Species / Q000378:metabolism*
D000959:Antihypertensive Agents; D002227:Carbazoles; D010982:Platelet-Derived Growth Factor; D011412:Propanolamines; D017382:Reactive Oxygen Species; D000077261:Carvedilol; D020928:Mitogen-Activated Protein Kinases