Promyelocytic Leukemia Zinc Finger Protein Activates GATA4 Transcription and Mediates Cardiac Hypertrophic Signaling from Angiotensin II Receptor 2

Abstract

BackgroundPressure overload and prolonged angiotensin II (Ang II) infusion elicit cardiac hypertrophy in Ang II receptor 1 (AT1) null mouse, whereas Ang II receptor 2 (AT2) gene deletion abolishes the hypertrophic response. The roles and signals of the cardiac AT2 receptor still remain unsettled. Promyelocytic leukemia zinc finger protein (PLZF) was shown to bind to the AT2 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.Methodology and Principal FindingsPLZF 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 AT2 receptor blocker given to Ang II-infused wild type mice prevented hypertrophy, verifying the role of AT2 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.ConclusionsPLZF is an important AT2 receptor binding protein in mediating Ang II induced cardiac hypertrophy through an AT2 receptor-dependent signal pathway. The angiotensin II-AT2-PLZF-GATA4 signal may further augment Ang II induced pathological effects on cardiomyocytes.

Angiotensin II/Angiotensin II Receptor Blockade Affects Osteoporosis via the AT1/AT2-Mediated cAMP-Dependent PKA Pathway

“…The reason for such a discrepancy may be due to the various kinds of AT1/AT2 receptor blockades, personalized administration of drugs including drug dosage and different delivery methods, sex of mice or rats, and the variance in pathological status and severity. As members of the G-protein-coupled receptor family, the AT1 and AT2 receptors share a limited sequence homology (34% amino acid sequence identity) and thus respond differently to AngII at various concentrations in the context of the concrete biological environment [Senbonmatsu et al, 2003;Wang et al, 2012]. We thus hypothesized that exogenous AngII or different kinds and concentrations of ARB1/2 may affect the functions of these 2 receptors differently and subsequently induce different biological responses in bone.…”

The angiotensin II type 2 receptor agonist Compound 21 is protective in experimental diabetes-associated atherosclerosis

“…More recently, the diverse cardiac response associated with the AT 2 R has also been shown to be dependent on the transcription factors with which it interacts. The ability of the AT 2 R to bind and facilitate the translocation of promyelocytic leukaemia zinc finger transcription factor to the nucleus has been shown to be implicated in driving its hypertrophic activity in response to Ang II [39].…”

Direct renin inhibition prevents cardiac dysfunction in a diabetic mouse model: comparison with an angiotensin receptor antagonist and angiotensin-converting enzyme inhibitor

“…This interaction caused nuclear translocation of PLZF resulting in negative regulation on PRR and positive regulation of PI3K-p85 expression (56). Studies in the heart reported direct interaction of PLZF with the AT 2 receptor, which resulted in Ang II-induced nuclear localization of PLZF and enhanced expression of PI3K-p85 and GATA4 (57, 58). In other systems, PLZF targets included smooth muscle α-actin in chicken embryonic fibroblasts, Redd1 in spermatogonial progenitor cells, and c-myc in several cell lines (59, 60).…”