Nifedipine inhibited angiotensin II-induced monocyte chemoattractant protein 1 expression: involvement of inhibitor of nuclear factor kappa B kinase and nuclear factor kappa B-inducing kinase.
OBJECTIVE
The effect of nifedipine, a 1,4-dihydropyridine calcium antagonist, on the expression of monocyte chemoattractant protein 1 (MCP-1) induced by angiotensin II (Ang II) was examined using vascular smooth muscle cells (VSMC) isolated from rat thoracic aorta.


RESULTS
Ang II increased the expression of MCP-1 messenger RNA accompanied by an increase in nuclear factor kappa B (NF-kappaB) binding activity to the cis DNA element in the promoter region of MCP-1. Ang II also decreased the cytosolic level of the inhibitor of NF-kappaB (IkappaB) and increased the phosphorylation of IkappaB subunits, IkappaBalpha and IkappaBbeta, as well as the phosphorylation of IkappaB kinase (IKK) subunits, IKKalpha and IKKbeta, suggesting that Ang II enhanced the breakdown of IkappaB. Nifedipine decreased MCP-1 mRNA expression, together with NF-kappaB binding activity to the promoter region of MCP-1 induced by Ang II. Nifedipine also attenuated the decrease in the cytosolic level of IkappaB, and the phosphorylation of IkappaB and IKK subunits induced by Ang II. Moreover, Ang II increased the phosphorylation of NF-kappaB-inducing kinase (NIK), and this increase was significantly inhibited by nifedipine.


CONCLUSIONS
As NIK is reported to activate IKK, our results suggest that nifedipine attenuates the effect of Ang II on MCP-1 expression in VSMC by regulating the activity of NF-kappaB through NIK, IKK and IkappaB.
Wu
Lan
L
Department of Molecular and Cellular Biology, Division of Medical Biochemistry and Cardiovascular Biology, Ehime University School of Medicine, Shitsukawa, Tohon, Ehime 791-0295, Japan.
Iwai
Masaru
M
Li
Zhen
Z
Li
Jian-Mei
JM
Mogi
Masaki
M
Horiuchi
Masatsugu
M
D000804:Angiotensin II / Q000494:pharmacology*; D000818:Animals; D001013:Aorta, Thoracic / Q000166:cytology; D015152:Blotting, Northern; D015153:Blotting, Western; D002478:Cells, Cultured; D018932:Chemokine CCL2 / Q000096:biosynthesis* / Q000235:genetics; D005786:Gene Expression Regulation / Q000187:drug effects* / Q000502:physiology; D051550:I-kappa B Kinase / Q000378:metabolism*; D008297:Male; D009131:Muscle, Smooth, Vascular / Q000166:cytology / Q000187:drug effects / Q000378:metabolism; D009543:Nifedipine / Q000494:pharmacology*; D011401:Promoter Regions, Genetic; D017346:Protein Serine-Threonine Kinases / Q000037:antagonists & inhibitors / Q000378:metabolism*; D012333:RNA, Messenger / Q000378:metabolism; D051381:Rats; D017207:Rats, Sprague-Dawley; D044140:Receptor, Angiotensin, Type 1 / Q000187:drug effects / Q000502:physiology; D020133:Reverse Transcriptase Polymerase Chain Reaction; D000097782:NF-kappaB-Inducing Kinase
D000804:Angiotensin II; D018932:Chemokine CCL2; D051550:I-kappa B Kinase; D009543:Nifedipine; D017346:Protein Serine-Threonine Kinases; D012333:RNA, Messenger; D044140:Receptor, Angiotensin, Type 1; D000097782:NF-kappaB-Inducing Kinase; C491766:Ccl2 protein, rat