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

Abstract

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.

Serum protein signature of coronary artery disease in type 2 diabetes mellitus

“…Further, leptin is able to induce production of C-reactive protein by endothelial cells [24]. The increase local availability of leptin in the vascular wall can in turn exert pro-atherothrombotic effects both on endothelial cells and smooth muscle cells [25, 26].…”

Isoflavone Ameliorated Oxidative Stress and Vascular Damages in Nicotine-Administrated Mice

“…Thus, isoflavone evidently inhibits both MMP-2 overproduction and elastin destruction, thereby exerting a protective effect against the progression of vascular injury. The capacity of isoflavone to suppress MMP-2 expression may be associated with the inhibition of p44/42 mitogen-activated protein kinases MAPK pathways 25 and nuclear factor kappa B NF-κB activities 26 .…”

“…Thirty-one young, adult male C57BL/6 mice, aged 3 weeks, were obtained from Japan SLC, Inc., Shizuoka, Japan. The mice were randomly placed in separate cages, under controlled conditions of a 12 h light/dark cycle at 25 1 . Prior approval for all animal experiments was obtained from the Kindai University Animal Care and Use Committee and the trials were carried out according to Kindai University Animal Experimentation Regulations approval number; KAAG-25-002 .…”

Leptin in Atherosclerosis: Focus on Macrophages, Endothelial and Smooth Muscle Cells

“…SMC migration and proliferation are key events central to the progression of atherosclerosis. A growing body of literature [ 39 , 42 , 105 , 106 , 107 , 108 ] supports the growth-promoting effects of leptin on VSMC that may likely attribute to leptin-induced neointimal growth, vessel remodeling and atherosclerosis. Previous studies have reported that leptin stimulates VSMC proliferation via increased cell cycle progression to S and G2/M phases accompanied with augmented ERK1/2 and NF-kB activation [ 105 ].…”

“…Previous studies have reported that leptin stimulates VSMC proliferation via increased cell cycle progression to S and G2/M phases accompanied with augmented ERK1/2 and NF-kB activation [ 105 ]. Leptin-induced cell cycle regulation has been shown to be mediated via increased expression of Cyclin D1 and β-catenin (regulator of cell–cell adhesion) concomitant to reduced p21 WAF1/Cip1 (promotes cell cycle arrest) [ 107 , 108 ] expression. Leptin has also been documented to increase VSMC migration mediated via enhanced matrix metalloproteinase-9 (MMP-9) expression [ 107 ].…”