Inhibition of neointimal hyperplasia development by MCI-186 is correlated with downregulation of nuclear factor-kappaB pathway.
BACKGROUND
Atherosclerosis is a progressing inflammatory response mediated by various signaling molecules among which nuclear factor kappaB (NF-kappaB) is thought to have a pivotal role. This study demonstrated the efficacy of antioxidant MCI-186 in preventing the progression of atherosclerosis by inhibiting signaling molecules such as NF-kappaB.


RESULTS
Balloon injury of intima was performed in the right common carotid artery of Japanese male white rabbits, which were then fed a 1% high cholesterol diet for 4 weeks, after assigning them to either the control (n=7) or MCI-186 (0.5 mg .kg(-1) . day(-1), n=7) group. Histological analysis revealed a reduction in neointimal thickness and lipid deposition in the subendothelial area of the MCI-186 group. Immunohistochemical analysis revealed attenuation of E-selectin expression, macrophage migration and proliferation of smooth muscle cells in the MCI-186 treated group. In in vitro studies, rabbit aorta smooth muscle cells were incubated with rIL-1betain either the presence or absence of MCI-186. MCI-186 significantly inhibited rIL-1beta-induced proliferation of smooth muscle cells from rabbit aorta, as well as the activation of NF-kappaB. Moreover, western blot analysis showed the inhibitory action of MCI-186 on the nuclear translocation of NF-kappaB in human umbilical vein endothelial cells under rIL-1betastimulation.


CONCLUSIONS
MCI-186 could provide a novel therapeutic strategy for atherosclerosis by inhibiting the NF-kappaB pathway.
Radhakrishnan
Geethalakshmi
G
Department of Surgery II, Faculty of Medicine, Kochi University, Nankoku, Japan.
Suzuki
Ryoko
R
Maeda
Hironori
H
Yamamoto
Morio
M
Hirose
Nobuyuki
N
Gopalrao
Rajesh Katare
RK
Lee
Gang-Hang
GH
Hayashi
Yoshihiro
Y
Rao
Parijatha
P
Sasaguri
Shiro
S
D000800:Angioplasty, Balloon / Q000009:adverse effects; D000818:Animals; D000975:Antioxidants / Q000378:metabolism; D000983:Antipyrine / Q000031:analogs & derivatives* / Q000494:pharmacology; D002340:Carotid Artery Diseases / Q000378:metabolism / Q000473:pathology* / Q000517:prevention & control*; D020212:Carotid Artery Injuries / Q000378:metabolism / Q000473:pathology; D017536:Carotid Artery, Common / Q000378:metabolism / Q000473:pathology; D002784:Cholesterol / Q000097:blood; D004195:Disease Models, Animal; D015536:Down-Regulation / Q000187:drug effects; D019040:E-Selectin / Q000378:metabolism; D000077553:Edaravone; D016166:Free Radical Scavengers / Q000494:pharmacology*; D006965:Hyperplasia; D020672:I-kappa B Proteins / Q000378:metabolism; D053583:Interleukin-1beta / Q000494:pharmacology; D008297:Male; D000072000:NF-KappaB Inhibitor alpha; D016328:NF-kappa B / Q000378:metabolism*; D011817:Rabbits; D015398:Signal Transduction / Q000187:drug effects; D013481:Superoxides / Q000378:metabolism; D017539:Tunica Intima / Q000378:metabolism / Q000473:pathology
D000975:Antioxidants; D019040:E-Selectin; D016166:Free Radical Scavengers; D020672:I-kappa B Proteins; D053583:Interleukin-1beta; D016328:NF-kappa B; C000606204:NFKBIA protein, human; D013481:Superoxides; D000072000:NF-KappaB Inhibitor alpha; D002784:Cholesterol; D000077553:Edaravone; D000983:Antipyrine