title: Oestrogen inhibits BMP4-induced BMP4 expression in cardiomyocytes: a potential mechanism of oestrogen-mediated protection against cardiac hypertrophy.
abstract: OBJECTIVE
  Oestrogen inhibits cardiac hypertrophy and bone morphogenetic protein-4 (BMP4) induces cardiac hypertrophy. Here we have studied the inhibition by oestrogen of BMP4 expression in cardiomyocytes.
  
  
  METHODS
  Cultures of neonatal rat cardiomyocytes were used in in vitro experiments. Bilatαl ovariectomy (OVX) was carried out in female Kunming mice and cardiac hypertrophy was induced by transverse aortic constriction (TAC).
  
  
  RESULTS
  Oestrogen inhibited BMP4-induced cardiomyocyte hypertrophy and BMP4 expression in vitro. The inhibition of BMP4-induced BMP4 protein expression by oestrogen was prevented by the inhibitor of oestrogen receptor-β, PHTPP, but not by the inhibitor of oestrogen receptor-α MPP. BMP4 induced smad1/5/8 activation, which was not affected by oestrogen in cardiomyocytes. BMP4 induced JNK but not ERK1/2 and p38 activation, and activated JNK was inhibited by oestrogen. Treatment with the p38 inhibitor SB203580 or the JNK inhibitor SP600125 inhibited BMP4-induced BMP4 expression in cardiomyocytes, but the ERK1/2 inhibitor U0126 increased BMP4-induced BMP4 expression, indicating that JNK, ERK1/2 and p38 MAPKs were all involved, although only JNK activation contributed to the inhibition of BMP4-induced BMP4 expression by oestrogen. TAC induced significant heart hypertrophy in OVX mice in vivo and oestrogen replacement inhibited TAC-induced heart hypertrophy in OVX mice. In parallel with the data of heart hypertrophy, oestrogen replacement significantly reduced the increased BMP4 protein expression in TAC-treated OVX mice.
  
  
  CONCLUSIONS
  Oestrogen treatment inhibited BMP4-induced BMP4 expression in cardiomyocytes through stimulating oestrogen receptor-β and inhibiting JNK activation. Our results provide a novel mechanism underlying oestrogen-mediated protection against cardiac hypertrophy.
authors.affiliation: Department of Pharmacology (the State-Province Key Laboratories of Biomedicine-Pharmaceutics of China, Key Laboratory of Cardiovascular Research, Ministry of Education), Harbin Medical University, Harbin, China.
authors.forename: Yu-Chun
authors.initials: YC
authors.lastname: Wang
authors.affiliation: Department of Pharmacology (the State-Province Key Laboratories of Biomedicine-Pharmaceutics of China, Key Laboratory of Cardiovascular Research, Ministry of Education), Harbin Medical University, Harbin, China.
authors.forename: Xiao-Lin
authors.initials: XL
authors.lastname: Xiao
authors.affiliation: Department of Pharmacology (the State-Province Key Laboratories of Biomedicine-Pharmaceutics of China, Key Laboratory of Cardiovascular Research, Ministry of Education), Harbin Medical University, Harbin, China.
authors.forename: Na
authors.initials: N
authors.lastname: Li
authors.affiliation: Department of Pharmacology (the State-Province Key Laboratories of Biomedicine-Pharmaceutics of China, Key Laboratory of Cardiovascular Research, Ministry of Education), Harbin Medical University, Harbin, China.
authors.forename: Di
authors.initials: D
authors.lastname: Yang
authors.affiliation: Department of Pharmacology (the State-Province Key Laboratories of Biomedicine-Pharmaceutics of China, Key Laboratory of Cardiovascular Research, Ministry of Education), Harbin Medical University, Harbin, China.
authors.forename: Yue
authors.initials: Y
authors.lastname: Xing
authors.affiliation: Department of Pharmacology (the State-Province Key Laboratories of Biomedicine-Pharmaceutics of China, Key Laboratory of Cardiovascular Research, Ministry of Education), Harbin Medical University, Harbin, China.
authors.forename: Rong
authors.initials: R
authors.lastname: Huo
authors.affiliation: Department of Pharmacology (the State-Province Key Laboratories of Biomedicine-Pharmaceutics of China, Key Laboratory of Cardiovascular Research, Ministry of Education), Harbin Medical University, Harbin, China.
authors.forename: Ming-Yu
authors.initials: MY
authors.lastname: Liu
authors.affiliation: Department of Pharmacology (the State-Province Key Laboratories of Biomedicine-Pharmaceutics of China, Key Laboratory of Cardiovascular Research, Ministry of Education), Harbin Medical University, Harbin, China.
authors.forename: Yan-Qiu
authors.initials: YQ
authors.lastname: Zhang
authors.affiliation: Department of Pharmacology (the State-Province Key Laboratories of Biomedicine-Pharmaceutics of China, Key Laboratory of Cardiovascular Research, Ministry of Education), Harbin Medical University, Harbin, China.
authors.forename: De-Li
authors.initials: DL
authors.lastname: Dong
mesh_terms: D000818:Animals; D055415:Bone Morphogenetic Protein 4 / Q000096:biosynthesis / Q000235:genetics* / Q000378:metabolism*; D006332:Cardiomegaly / Q000378:metabolism / Q000517:prevention & control*; D002478:Cells, Cultured; D004789:Enzyme Activation / Q000187:drug effects; D047629:Estrogen Receptor beta / Q000378:metabolism; D004967:Estrogens / Q000008:administration & dosage / Q000494:pharmacology*; D005260:Female; D005786:Gene Expression Regulation / Q000187:drug effects*; D007279:Injections, Subcutaneous; D048031:JNK Mitogen-Activated Protein Kinases / Q000037:antagonists & inhibitors / Q000378:metabolism; D051379:Mice; D008815:Mice, Inbred Strains; D032383:Myocytes, Cardiac / Q000187:drug effects* / Q000378:metabolism; D051381:Rats; D013329:Structure-Activity Relationship
chemical_list: C525810:Bmp4 protein, mouse; D055415:Bone Morphogenetic Protein 4; D047629:Estrogen Receptor beta; D004967:Estrogens; D048031:JNK Mitogen-Activated Protein Kinases