Metformin inhibits nuclear factor kappaB activation and decreases serum high-sensitivity C-reactive protein level in experimental atherogenesis of rabbits.
Previous studies demonstrated that metformin has obvious antiatherogenic properties, but the exact mechanism remains unclear. Therefore, we established an atherosclerotic rabbit model in order to investigate the potential effects of metformin on transcription factor nuclear factor kappaB (NF-kappaB) and serum high-sensitivity C-reactive protein (hs-CRP) level, which had been regarded as proatherogenic factors. New Zealand rabbits were randomly divided into three groups: a control group (n = 8), an atherosclerotic group (AS group, n = 8), and a metformin treatment group (Met group, n = 8). The experimental atherosclerotic rabbit model was successfully established at the end of the 8th week. From the 9th week, rabbits in the Met group were administered with 150 mg/kg metformin daily by gavage. Blood samples were collected at days 0 and 8, and at 16 weeks to detect the level of blood lipid and serum glucose. At the end of the experiment, blood samples were withdrawn for determining serum hs-CRP. Aortic samples were harvested for histomorphometric analysis. Immunohistochemistry and Western blotting were used to detect the expression of NF-kappaB subunit p65 in nuclear extracts and phosphorylation of inhibitor of nuclear factor kappaB (IkappaB) in cytoplasmic extracts. An experimental atherosclerotic rabbit model was successfully established. The expression of nuclear NF-kappaB subunit p65 and cytoplasmic phosphorylation of IkappaB protein in the vessel wall was enhanced (P < 0.01, respectively) in the AS group, and serum hs-CRP level was significantly increased in the AS group compared with the control group (3.90 +/- 0.25 mg/l versus 1.36 +/- 0.14 mg/l, P < 0.01). Treatment with metformin significantly attenuated the progression of aortic atherosclerosis. In the Met group, there was a marked reduction in nuclear NF-kappaB subunit p65 and cytoplasmic phosphorylation of IkappaB protein expression (P < 0.01). Serum hs-CRP concentration was also significantly decreased (3.20 +/- 0.20 mg/l versus 3.90 +/- 0.25 mg/l, P < 0.05). Metformin inhibits the phosphorylation of IkappaB and the activation of NF-kappaB in the vessel wall of experimental atherogenesis of rabbits, as well as decreasing the serum level of hs-CRP, thus suggesting that metformin has vascular anti-inflammatory properties, which may be one of its antiatherogenic mechanisms.
Li
Song-Nan
SN
Department of Cardiology, Institute of Cardiology, Union Hospital, Huazhong University of Science and Technology, Wuhan 430022, PR China.
Wang
Xiang
X
Zeng
Qiu-Tang
QT
Feng
Yi-Bai
YB
Cheng
Xiang
X
Mao
Xiao-Bo
XB
Wang
Tian-Hong
TH
Deng
He-Ping
HP
D000818:Animals; D000893:Anti-Inflammatory Agents / Q000494:pharmacology*; D001011:Aorta / Q000000981:diagnostic imaging / Q000187:drug effects* / Q000378:metabolism / Q000473:pathology; D050197:Atherosclerosis / Q000188:drug therapy* / Q000378:metabolism / Q000473:pathology; D015415:Biomarkers / Q000097:blood; D001786:Blood Glucose / Q000187:drug effects; D015153:Blotting, Western; D002097:C-Reactive Protein / Q000378:metabolism*; D004195:Disease Models, Animal; D015536:Down-Regulation; D020672:I-kappa B Proteins / Q000378:metabolism; D007150:Immunohistochemistry; D008055:Lipids / Q000097:blood; D008297:Male; D008687:Metformin / Q000494:pharmacology*; D010766:Phosphorylation; D011817:Rabbits; D013997:Time Factors; D051996:Transcription Factor RelA / Q000378:metabolism*; D014463:Ultrasonography
D000893:Anti-Inflammatory Agents; D015415:Biomarkers; D001786:Blood Glucose; D020672:I-kappa B Proteins; D008055:Lipids; D051996:Transcription Factor RelA; D002097:C-Reactive Protein; D008687:Metformin