Promyelocytic leukemia zinc finger protein activates GATA4 transcription and mediates cardiac hypertrophic signaling from angiotensin II receptor 2

• Published in: PloS one Vol. 7; no. 4; p. e35632
• Main Authors: Wang, Ning, Frank, Gerald D, Ding, Ronghua, Tan, Zhongjia, Rachakonda, Amita, Pandolfi, Pier Paolo, Senbonmatsu, Takaaki, Landon, Erwin J, Inagami, Tadashi
• Format: Journal Article
• Language: English
• Published: United States Public Library of Science 27-04-2012; Public Library of Science (PLoS)
• Subjects: Angiotensin AT2 receptors; Angiotensin II; Angiotensin II - administration & dosage; Angiotensin II - adverse effects; Angiotensin II Type 2 Receptor Blockers - administration & dosage; Angiotensins; Animals; Binding Sites; Biochemistry; Biology; Blood pressure; Blood Pressure - drug effects; Cardiomegaly - chemically induced; Cardiomegaly - complications; Cardiomegaly - metabolism; Cardiomegaly - physiopathology; Cardiomyocytes; Cardiomyopathy; Chromatin; Coronary vessels; Diet therapy; DNA binding proteins; Electrophoretic mobility; Endocrinology; Fibrosis; Fibrosis - chemically induced; Fibrosis - complications; Fibrosis - metabolism; Fibrosis - physiopathology; Gata4 gene; GATA4 Transcription Factor - genetics; GATA4 Transcription Factor - metabolism; Gene deletion; Gene expression; Gene Expression Regulation - drug effects; Genes; Heart; Heart - drug effects; Heart - physiopathology; Heart diseases; Heart failure; Heart hypertrophy; Hypertension; Hypertrophy; Hypoglycemia; Hypotheses; Immunoprecipitation; Kinases; Kruppel-Like Transcription Factors - deficiency; Kruppel-Like Transcription Factors - genetics; Leukemia; Male; Medicine; Mice; Mice, Knockout; Myocytes, Cardiac - drug effects; Myocytes, Cardiac - metabolism; Myocytes, Cardiac - pathology; Pathological effects; Pathology; Physicians; Promyelocytic Leukemia Zinc Finger Protein; Promyeloid leukemia; Protein Binding; Proteins; Receptor, Angiotensin, Type 2 - genetics; Receptor, Angiotensin, Type 2 - metabolism; Rodents; Signal Transduction - drug effects; Signal Transduction - genetics; Signaling; Stem cells; Transcription (Genetics); Transcription factors; Transcription, Genetic - drug effects; Transgenic animals; Zinc; Zinc finger proteins; United States > US; Tennessee; Nashville Tennessee
• ISSN: 1932-6203; 1932-6203
• DOI: 10.1371/journal.pone.0035632

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.
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.
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.