Tsai Yung-Chieh, Leu Sy-Ying, Peng Yi-Jen, Lee Yen-Mei, Hsu Chih-Hsiung, Chou Shen-Chieh, Yen Mao-Hsiung, Cheng Pao-Yun
Department of Obstetrics and Gynecology, Chi-Mei Medical Center, Tainan, Taiwan.
Department of Medicine, Taipei Medical University, Taipei, Taiwan.
J Cell Mol Med. 2017 Mar;21(3):422-431. doi: 10.1111/jcmm.12986. Epub 2016 Sep 28.
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.
肥胖是心血管疾病发生的一个重要危险因素，并且与循环中瘦素浓度的显著升高有关。瘦素是一种主要由脂肪组织产生的肽类激素，受能量水平、激素及多种炎症介质调节。染料木黄酮是一种具有多种促进健康作用的异黄酮。在此，我们研究了染料木黄酮是否能抑制瘦素诱导的致动脉粥样硬化作用。用瘦素和/或染料木黄酮处理A10细胞，然后分析细胞增殖和迁移情况。还检测了活性氧（ROS）和蛋白质水平，如p44/42MAPK、细胞周期相关蛋白（细胞周期蛋白D1和p21）以及基质金属蛋白酶-2（MMP-2）。采用免疫组织化学和形态计量学分析大鼠颈动脉损伤模型中的新生内膜形成情况。染料木黄酮（5 μM）显著抑制了瘦素（10 ng/ml）刺激的A10细胞的增殖和迁移。与这些发现一致，染料木黄酮降低了瘦素刺激的ROS产生以及p44/42MAPK信号转导通路的磷酸化。同时，染料木黄酮逆转了瘦素诱导的细胞周期蛋白D1及细胞周期蛋白依赖性激酶抑制剂p21的表达。染料木黄酮通过抑制MMP-2活性减弱了瘦素诱导的A10细胞迁移。此外，与球囊损伤加瘦素组相比，在染料木黄酮（5 mg/kg体重）处理组中，瘦素（0.25 mg/kg）增强的大鼠颈动脉损伤模型中的新生内膜形成得到了减弱。染料木黄酮能够在体外和体内抑制瘦素的致动脉粥样硬化作用，可能是临床应用中有前景的候选药物。
