J Korean Soc Vasc Surg.  2002 Apr;18(1):15-22.

Effect of Carvedilol on Human Vascular Smooth Muscle Cell Proliferation and Its Signal Transduction

• Park J
• Ha H
• Oh JW
• Kim MS
• Seo J
• Kim HJ
• Park K
• Kim YS

Abstract

PURPOSE: Vascular smooth muscle cells (VSMCs) migration and proliferation play important roles in transplant vascular sclerosis and restenosis after balloon vascular injury. The anti-proliferative and anti- migratory effects of carvedilol (CA), a unique alpha- and beta-blocking anti-hypertensive drug, on the VSMCs were confirmed previously. Since reactive oxygen species (ROS) and mitogen-activated protein kinases (MAPK) family play important roles in proliferation of VSMCs, the present study examined the effects of CA on intracellular ROS generation, activation of ERK1/2 and p38 MAPK, and proliferation of VSMCs cultured under platelet derived growth factor (PDGF).
METHODS
Human VSMCs obtained from ATCC were cultured with RPMI-1640 containing 10% fetal bovine serum. Near confluent VSMCs were incubated with serum-free media for 48 hours to arrest and synchronize the cell growth. CA was administered 1 hour before the addition of PDGF. 5-(and-6)-chloromethyl-2',7'-dichlorodihydrofluorescein (DCF)-sensitive intracellular ROS was detected by FACS. Activations of ERK1/2 and p38 MAPK were measured by Western blot analysis. Proliferation of VSMCs was assessed by [3H]-thymidine incorporation.
RESULTS
PDGF at 10 ng/ml, which induced human VSMCs proliferation, rapidly increased intracellular ROS by 1.6-fold (P<0.01), ERK1/2 activation by 2.1-fold (P<0.01), and p38 MAPK activation by 1.9-fold (P<0.01), respectively, as compared to the control. CA 1 and 10muM effectively inhibited PDGF-induced human VSMCs proliferation. CA also effectively inhibited PDGF-induced intracellular ROS generation as well as ERK1/2 and P38 MAPK activation.
CONCLUSION
The present study suggests that CA inhibits PDGF-induced human VSMCs proliferation, possibly by inhibiting intracellular ROS generation and activation of ERK1/2 and p38 MAPK.

Keyword

Carvedilol; Vascular; Smooth muscle cell; Reactive oxygen; Mitogen-activated protein kinases

MeSH Terms

Blotting, Western
Cell Proliferation*
Culture Media, Serum-Free
Humans*
Mitogen-Activated Protein Kinases
Muscle, Smooth, Vascular*
Myocytes, Smooth Muscle
p38 Mitogen-Activated Protein Kinases
Platelet-Derived Growth Factor
Reactive Oxygen Species
Sclerosis
Signal Transduction*
Vascular System Injuries
Culture Media, Serum-Free
Mitogen-Activated Protein Kinases
Platelet-Derived Growth Factor
Reactive Oxygen Species
p38 Mitogen-Activated Protein Kinases