title: Genistein alleviates pressure overload-induced cardiac dysfunction and interstitial fibrosis in mice.
abstract: OBJECTIVE
  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.
  
  
  METHODS
  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.
  
  
  RESULTS
  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.
  
  
  CONCLUSIONS
  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.
authors.affiliation: 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.
authors.forename: Wei
authors.initials: W
authors.lastname: Qin
authors.affiliation: 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.
authors.forename: Ning
authors.initials: N
authors.lastname: Du
authors.affiliation: 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.
authors.forename: Longyin
authors.initials: L
authors.lastname: Zhang
authors.affiliation: 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.
authors.forename: Xianxian
authors.initials: X
authors.lastname: Wu
authors.affiliation: 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.
authors.forename: Yingying
authors.initials: Y
authors.lastname: Hu
authors.affiliation: 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.
authors.forename: Xiaoguang
authors.initials: X
authors.lastname: Li
authors.affiliation: 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.
authors.forename: Nannan
authors.initials: N
authors.lastname: Shen
authors.affiliation: 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.
authors.forename: Yang
authors.initials: Y
authors.lastname: Li
authors.affiliation: 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.
authors.forename: Baofeng
authors.initials: B
authors.lastname: Yang
authors.affiliation: 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.
authors.forename: Chaoqian
authors.initials: C
authors.lastname: Xu
authors.affiliation: 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.
authors.forename: Zhiwei
authors.initials: Z
authors.lastname: Fang
authors.affiliation: 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.
authors.forename: Yanjie
authors.initials: Y
authors.lastname: Lu
authors.affiliation: 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.
authors.forename: Yong
authors.initials: Y
authors.lastname: Zhang
authors.affiliation: Institute of Clinical Pharmacy, The Second Affiliated Hospital of Harbin Medical University, Harbin, Heilongjiang, China.
authors.forename: Zhimin
authors.initials: Z
authors.lastname: Du
mesh_terms: D000284:Administration, Oral; D000818:Animals; D004305:Dose-Response Relationship, Drug; D005355:Fibrosis / Q000188:drug therapy* / Q000378:metabolism; D019833:Genistein / Q000008:administration & dosage / Q000627:therapeutic use*; D006333:Heart Failure / Q000188:drug therapy* / Q000378:metabolism; D048031:JNK Mitogen-Activated Protein Kinases / Q000037:antagonists & inhibitors / Q000378:metabolism; D048670:MAP Kinase Kinase 4 / Q000037:antagonists & inhibitors / Q000378:metabolism; D020930:MAP Kinase Kinase Kinases / Q000037:antagonists & inhibitors / Q000378:metabolism; D008297:Male; D051379:Mice; D008815:Mice, Inbred Strains; D015394:Molecular Structure; D009363:Neoplasm Proteins / Q000037:antagonists & inhibitors / Q000378:metabolism; D011312:Pressure; D013329:Structure-Activity Relationship; D000099151:MAP Kinase Kinase Kinase 7
chemical_list: D019833:Genistein; D048031:JNK Mitogen-Activated Protein Kinases; D048670:MAP Kinase Kinase 4; D020930:MAP Kinase Kinase Kinases; D009363:Neoplasm Proteins; D000099151:MAP Kinase Kinase Kinase 7; C435499:Mta3 protein, mouse