Genistein suppresses leptin-induced proliferation and migration of vascular smooth muscle cells and neointima formation.
Obesity is a strong risk factor for the development of cardiovascular diseases and is associated with a marked increase in circulating leptin concentration. Leptin is a peptide hormone mainly produced by adipose tissue and is regulated by energy level, hormones and various inflammatory mediators. Genistein is an isoflavone that exhibits diverse health-promoting effects. Here, we investigated whether genistein suppressed the atherogenic effect induced by leptin. The A10 cells were treated with leptin and/or genistein, and then the cell proliferation and migration were analysed. The reactive oxygen species (ROS) and proteins levels were also measured, such as p44/42MAPK, cell cycle-related protein (cyclin D1 and p21) and matrix metalloproteinase-2 (MMP-2). Immunohistochemistry and morphometric analysis were used for the neointima formation in a rat carotid artery injury model. Genistein (5 μM) significantly inhibited both the proliferation and migration of leptin (10 ng/ml)-stimulated A10 cells. In accordance with these finding, genistein decreased the leptin-stimulated ROS production and phosphorylation of the p44/42MAPK signal transduction pathway. Meanwhile, genistein reversed the leptin-induced expression of cyclin D1, and cyclin-dependent kinase inhibitor, p21. Genistein attenuated leptin-induced A10 cell migration by inhibiting MMP-2 activity. Furthermore, the leptin (0.25 mg/kg)-augmented neointima formation in a rat carotid artery injury model was attenuated in the genistein (5 mg/kg body weight)-treated group when compared with the balloon injury plus leptin group. Genistein was capable of suppressing the atherogenic effects of leptin in vitro and in vivo, and may be a promising candidate drug in the clinical setting.
Department of Obstetrics and Gynecology, Chi-Mei Medical Center, Tainan, Taiwan.|Department of Medicine, Taipei Medical University, Taipei, Taiwan.|Department of Sport Management, Chia Nan University of Pharmacy and Science, Tainan, Taiwan.
Yung-Chieh
YC
Tsai
Graduate Institute of Life Sciences, National Defense Medical Center, Taipei, Taiwan.
Sy-Ying
SY
Leu
Department of Pathology, Tri-Service General Hospital and National Defense Medical Center, Taipei, Taiwan.
Yi-Jen
YJ
Peng
Department of Pharmacology, National Defense Medical Center, Taipei, Taiwan.
Yen-Mei
YM
Lee
Department of Internal Medicine, Tri-Service General Hospital, National Defense Medical Center, Taipei, Taiwan.
Chih-Hsiung
CH
Hsu
Department of Biological Science and Technology, College of Biopharmaceutical and Food Sciences, China Medical University, Taichung, Taiwan.
Shen-Chieh
SC
Chou
Department of Pharmacology, National Defense Medical Center, Taipei, Taiwan.
Mao-Hsiung
MH
Yen
Department of Physiology and Biophysics, Graduate Institute of Physiology, National Defense Medical Center, Taipei, Taiwan.
Pao-Yun
PY
Cheng
D000818:Animals; D020212:Carotid Artery Injuries / Q000188:drug therapy / Q000378:metabolism; D002465:Cell Movement / Q000187:drug effects*; D049109:Cell Proliferation / Q000187:drug effects*; D019938:Cyclin D1 / Q000378:metabolism; D050759:Cyclin-Dependent Kinase Inhibitor p21 / Q000378:metabolism; D019833:Genistein / Q000494:pharmacology*; D020738:Leptin / Q000494:pharmacology*; D008297:Male; D020778:Matrix Metalloproteinase 2 / Q000378:metabolism; D009131:Muscle, Smooth, Vascular / Q000187:drug effects* / Q000378:metabolism; D032389:Myocytes, Smooth Muscle / Q000187:drug effects* / Q000378:metabolism; D058426:Neointima / Q000188:drug therapy* / Q000378:metabolism; D010766:Phosphorylation / Q000187:drug effects; D051381:Rats; D017207:Rats, Sprague-Dawley; D017382:Reactive Oxygen Species / Q000378:metabolism; D015398:Signal Transduction / Q000187:drug effects
D050759:Cyclin-Dependent Kinase Inhibitor p21; D020738:Leptin; D017382:Reactive Oxygen Species; D019938:Cyclin D1; D019833:Genistein; D020778:Matrix Metalloproteinase 2
Leptin; MMP2; carotid artery injury; genistein; reactive oxygen species
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