Genistein suppresses leptin‐induced proliferation and migration of vascular smooth muscle cells and neointima formation

• Published in: Journal of cellular and molecular medicine 2017-03, Vol.21 (3), p.422-431
• Main Authors: Tsai, Yung‐Chieh, Leu, Sy‐Ying, Peng, Yi‐Jen, Lee, Yen‐Mei, Hsu, Chih‐Hsiung, Chou, Shen‐Chieh, Yen, Mao‐Hsiung, Cheng, Pao‐Yun
• Format: Article
• Language: English
• Subjects: Adipose tissue; Angioplasty; Animals; Atherosclerosis; Balloon treatment; Body weight; Cardiovascular diseases; Carotid arteries; Carotid artery; Carotid Artery Injuries - drug therapy; Carotid Artery Injuries - metabolism; carotid artery injury; Cell adhesion & migration; Cell cycle; Cell growth; Cell migration; Cell Movement - drug effects; Cell proliferation; Cell Proliferation - drug effects; Cyclin D1; Cyclin D1 - metabolism; Cyclin-dependent kinase inhibitor p21; Cyclin-Dependent Kinase Inhibitor p21 - metabolism; Dehydrogenases; Endothelium; Enzyme inhibitors; Genistein; Genistein - pharmacology; GTP-binding protein; Health risks; Hypertension; Immunohistochemistry; Inflammation; Isoflavones; Laboratory animals; Leptin; Leptin - pharmacology; Male; Matrix metalloproteinase; Matrix Metalloproteinase 2 - metabolism; Menopause; Metalloproteinase; MMP2; Morphometry; Muscle, Smooth, Vascular - drug effects; Muscle, Smooth, Vascular - metabolism; Muscles; Myocytes, Smooth Muscle - drug effects; Myocytes, Smooth Muscle - metabolism; Neointima - drug therapy; Neointima - metabolism; Nitric oxide; Obesity; Original; Phosphorylation; Phosphorylation - drug effects; Proteins; R&D; Rats; Rats, Sprague-Dawley; Reactive oxygen species; Reactive Oxygen Species - metabolism; Research & development; Risk factors; Signal Transduction - drug effects; Smooth muscle; Studies; Veins & arteries
• ISSN: 1582-1838; 1582-4934
• DOI: 10.1111/jcmm.12986

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.