title: Promyelocytic leukemia zinc finger protein activates GATA4 transcription and mediates cardiac hypertrophic signaling from angiotensin II receptor 2.
abstract: BACKGROUND
  Pressure overload and prolonged angiotensin II (Ang II) infusion elicit cardiac hypertrophy in Ang II receptor 1 (AT(1)) null mouse, whereas Ang II receptor 2 (AT(2)) gene deletion abolishes the hypertrophic response. The roles and signals of the cardiac AT(2) receptor still remain unsettled. Promyelocytic leukemia zinc finger protein (PLZF) was shown to bind to the AT(2) receptor and transmit the hypertrophic signal. Using PLZF knockout mice we directed our studies on the function of PLZF concerning the cardiac specific transcription factor GATA4, and GATA4 targets.
  
  
  RESULTS
  PLZF knockout and age-matched wild-type (WT) mice were treated with Ang II, infused at a rate of 4.2 ng·kg(-1)·min(-1) for 3 weeks. Ang II elevated systolic blood pressure to comparable levels in PLZF knockout and WT mice (140 mmHg). WT mice developed prominent cardiac hypertrophy and fibrosis after Ang II infusion. In contrast, there was no obvious cardiac hypertrophy or fibrosis in PLZF knockout mice. An AT(2) receptor blocker given to Ang II-infused wild type mice prevented hypertrophy, verifying the role of AT(2) receptor for cardiac hypertrophy. Chromatin immunoprecipitation and electrophoretic mobility shift assay showed that PLZF bound to the GATA4 gene regulatory region. A Luciferase assay verified that PLZF up-regulated GATA4 gene expression and the absence of PLZF expression in vivo produced a corresponding repression of GATA4 protein.
  
  
  CONCLUSIONS
  PLZF is an important AT(2) receptor binding protein in mediating Ang II induced cardiac hypertrophy through an AT(2) receptor-dependent signal pathway. The angiotensin II-AT(2)-PLZF-GATA4 signal may further augment Ang II induced pathological effects on cardiomyocytes.
authors.affiliation: Department of Biochemistry, Vanderbilt University School of Medicine, Nashville, Tennessee, United States of America.
authors.forename: Ning
authors.initials: N
authors.lastname: Wang
authors.forename: Gerald D
authors.initials: GD
authors.lastname: Frank
authors.forename: Ronghua
authors.initials: R
authors.lastname: Ding
authors.forename: Zhongjia
authors.initials: Z
authors.lastname: Tan
authors.forename: Amita
authors.initials: A
authors.lastname: Rachakonda
authors.forename: Pier Paolo
authors.initials: PP
authors.lastname: Pandolfi
authors.forename: Takaaki
authors.initials: T
authors.lastname: Senbonmatsu
authors.forename: Erwin J
authors.initials: EJ
authors.lastname: Landon
authors.forename: Tadashi
authors.initials: T
authors.lastname: Inagami
mesh_terms: D000804:Angiotensin II / Q000008:administration & dosage / Q000009:adverse effects*; D057912:Angiotensin II Type 2 Receptor Blockers / Q000008:administration & dosage; D000818:Animals; D001665:Binding Sites; D001794:Blood Pressure / Q000187:drug effects; D006332:Cardiomegaly / Q000139:chemically induced / Q000150:complications / Q000378:metabolism* / Q000503:physiopathology; D005355:Fibrosis / Q000139:chemically induced / Q000150:complications / Q000378:metabolism* / Q000503:physiopathology; D050991:GATA4 Transcription Factor / Q000235:genetics* / Q000378:metabolism; D005786:Gene Expression Regulation / Q000187:drug effects; D006321:Heart / Q000187:drug effects / Q000503:physiopathology; D051741:Kruppel-Like Transcription Factors / Q000172:deficiency* / Q000235:genetics; D008297:Male; D051379:Mice; D018345:Mice, Knockout; D032383:Myocytes, Cardiac / Q000187:drug effects / Q000378:metabolism / Q000473:pathology; D000075722:Promyelocytic Leukemia Zinc Finger Protein; D011485:Protein Binding; D044139:Receptor, Angiotensin, Type 2 / Q000235:genetics / Q000378:metabolism*; D015398:Signal Transduction / Q000187:drug effects / Q000235:genetics; D014158:Transcription, Genetic / Q000187:drug effects
chemical_list: D057912:Angiotensin II Type 2 Receptor Blockers; D050991:GATA4 Transcription Factor; C484171:Gata4 protein, mouse; D051741:Kruppel-Like Transcription Factors; D000075722:Promyelocytic Leukemia Zinc Finger Protein; D044139:Receptor, Angiotensin, Type 2; C513267:Zbtb16 protein, mouse; D000804:Angiotensin II