Attenuation of monocyte chemoattractant protein-1 expression via inhibition of nuclear factor-kappaB activity in inflammatory vascular injury.
BACKGROUND
The effect of a calcium channel blocker (CCB) on the expression of monocyte chemoattractant protein (MCP)-1 was explored in inflammatory vascular injury, focusing on the role of nuclear factor (NF)-kappaB.


METHODS
Vascular injury was induced by cuff placement. Expression of MCP-1 was determined by real-time RT-PCR. NF-kappaB expression and its activity were detected by Western blot and electrophoretic mobility shift assay.


RESULTS
Polyethylene cuff placement around the mouse femoral artery increased MCP-1 expression, together with proliferation of vascular smooth muscle cells and neointimal formation in the injured artery. The content of NF-kappaB was decreased in the cytosolic fraction but increased in the nuclear fraction prepared from the injured artery. In the nuclear fraction, the binding activity of NF-kappaB to the promoter region of MCP-1 was markedly increased. On the other hand, IkappaB content in the cytosolic fraction was decreased in the injured artery after cuff placement, accompanied by an increase in IkappaB kinase (IKK) phosphorylation. Treatment of mice with a CCB, nifedipine, at a dose of 5 mg/kg/day, significantly decreased vascular smooth muscle cell proliferation and neointimal formation without affecting blood pressure. This dose of nifedipine inhibited the increase in MCP-1 expression in the injured artery. Moreover, nifedipine reduced the nuclear content and DNA-binding activity of NF-kappaB in the injured artery. In contrast, the decrease in IkappaB content and the increase in IKK phosphorylation in the cytosolic fraction were attenuated by nifedipine.


CONCLUSIONS
These results indicate that MCP-1 expression in inflammatory vascular injury is regulated by activation of NF-kappaB. The results also suggest that nifedipine attenuates MCP-1 expression in the injured artery via inhibition of the nuclear translocation and DNA-binding activity of NF-kappaB, and thereby improves vascular remodeling.
Gao
Xinyu
X
Department of Molecular Cardiovascular Biology and Pharmacology, Ehime University Graduate School of Medicine, Shitsukawa, Tohon, Ehime, Japan.
Iwai
Masaru
M
Inaba
Shinji
S
Tomono
Yumiko
Y
Kanno
Harumi
H
Mogi
Masaki
M
Horiuchi
Masatsugu
M
D000818:Animals; D001794:Blood Pressure / Q000187:drug effects; D001808:Blood Vessels / Q000473:pathology*; D002121:Calcium Channel Blockers / Q000494:pharmacology; D002467:Cell Nucleus / Q000187:drug effects / Q000378:metabolism; D049109:Cell Proliferation / Q000187:drug effects; D018932:Chemokine CCL2 / Q000096:biosynthesis*; D003600:Cytosol / Q000187:drug effects / Q000378:metabolism; D004247:DNA / Q000378:metabolism; D024202:Electrophoretic Mobility Shift Assay; D051550:I-kappa B Kinase / Q000037:antagonists & inhibitors; D007249:Inflammation / Q000473:pathology*; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D016328:NF-kappa B / Q000037:antagonists & inhibitors*; D009543:Nifedipine / Q000494:pharmacology; D012313:RNA / Q000096:biosynthesis / Q000235:genetics; D020133:Reverse Transcriptase Polymerase Chain Reaction
D002121:Calcium Channel Blockers; D018932:Chemokine CCL2; D016328:NF-kappa B; D012313:RNA; D004247:DNA; D051550:I-kappa B Kinase; D009543:Nifedipine