Qin Wei, Du Ning, Zhang Longyin, Wu Xianxian, Hu Yingying, Li Xiaoguang, Shen Nannan, Li Yang, Yang Baofeng, Xu Chaoqian, Fang Zhiwei, Lu Yanjie, Zhang Yong, Du Zhimin
Department of Pharmacology (State-Province Key Laboratories of Biomedicine-Pharmaceutics of China, Key Laboratory of Cardiovascular Research, Ministry of Education), Harbin Medical University, Harbin, Heilongjiang, China.
Institute of Cardiovascular Research, Harbin Medical University, Harbin, Heilongjiang, China.
Br J Pharmacol. 2015 Dec;172(23):5559-72. doi: 10.1111/bph.13002. Epub 2015 Jan 13.
Pressure overload-induced cardiac interstitial fibrosis is viewed as a major cause of heart failure in patients with hypertension or aorta atherosclerosis. The purpose of this study was to investigate the effects and the underlying mechanisms of genistein, a natural phytoestrogen found in soy bean extract, on pressure overload-induced cardiac fibrosis.
Genisten was administered to mice with pressure overload induced by transverse aortic constriction. Eight weeks later, its effects on cardiac dysfunction, hypertrophy and fibrosis were determined. Its effects on proliferation, collagen production and myofibroblast transformation of cardiac fibroblasts (CFs) and the signalling pathways were also assessed in vitro.
Pressure overload-induced cardiac dysfunction, hypertrophy and fibrosis were markedly attenuated by genistein. In cultured CFs, genistein inhibited TGFβ1-induced proliferation, collagen production and myofibroblast transformation. Genistein suppressed TGFβ-activated kinase 1 (TAK1) expression and produced anti-fibrotic effects by blocking the TAK1/MKK4/JNK pathway. Further analysis indicated that it up-regulated oestrogen-dependent expression of metastasis-associated gene 3 (MTA3), which was found to be a negative regulator of TAK1. Silencing MTA3 by siRNA, or inhibiting the activity of the MTA3-NuRD complex with trichostatin A, abolished genistein's anti-fibrotic effects.
Genistein improved cardiac function and inhibited cardiac fibrosis in response to pressure overload. The underlying mechanism may involve regulation of the MTA3/TAK1/MKK4/JNK signalling pathway. Genistein may have potential as a novel agent for prevention and therapy of cardiac disorders associated with fibrosis.
压力超负荷诱导的心脏间质纤维化被视为高血压或主动脉粥样硬化患者心力衰竭的主要原因。本研究旨在探讨大豆提取物中天然植物雌激素染料木黄酮对压力超负荷诱导的心脏纤维化的影响及其潜在机制。
对经主动脉缩窄诱导压力超负荷的小鼠给予染料木黄酮。8周后，测定其对心脏功能障碍、肥大和纤维化的影响。还在体外评估了其对心脏成纤维细胞（CFs）增殖、胶原蛋白产生和成肌纤维细胞转化以及信号通路的影响。
染料木黄酮显著减轻了压力超负荷诱导的心脏功能障碍、肥大和纤维化。在培养的CFs中，染料木黄酮抑制TGFβ1诱导的增殖、胶原蛋白产生和成肌纤维细胞转化。染料木黄酮抑制TGFβ激活激酶1（TAK1）表达，并通过阻断TAK1/MKK4/JNK途径产生抗纤维化作用。进一步分析表明，它上调了转移相关基因3（MTA3）的雌激素依赖性表达，发现该基因是TAK1的负调节因子。用siRNA沉默MTA3或用曲古抑菌素A抑制MTA3-NuRD复合物的活性，消除了染料木黄酮的抗纤维化作用。
染料木黄酮改善了压力超负荷引起的心脏功能并抑制了心脏纤维化。潜在机制可能涉及对MTA3/TAK1/MKK4/JNK信号通路的调节。染料木黄酮可能具有作为预防和治疗与纤维化相关心脏疾病的新型药物的潜力。
