Phosphorylation of GATA4 at serine105 is required for left ventricular remodelling process in angiotensin II–induced hypertension in rats

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Jurado Acosta , A , Rysä , J , Szabo , Z , Moilanen , A-M , Serpi , R & Ruskoaho , H 2020 , ' Phosphorylation of GATA4 at serine105 is required for left ventricular remodelling process in angiotensin II–induced hypertension in rats ' , Basic & Clinical Pharmacology & Toxicology , vol. 127 , no. 3 , pp. 178-195 . https://doi.org/10.1111/bcpt.13398

Title: Phosphorylation of GATA4 at serine105 is required for left ventricular remodelling process in angiotensin II–induced hypertension in rats
Author: Jurado Acosta, Alicia; Rysä, Jaana; Szabo, Zoltan; Moilanen, Anne-Mari; Serpi, Raisa; Ruskoaho, Heikki
Contributor organization: Division of Pharmacology and Pharmacotherapy
Drug Research Program
Regenerative pharmacology group
Date: 2020-09
Language: eng
Number of pages: 18
Belongs to series: Basic & Clinical Pharmacology & Toxicology
ISSN: 1742-7835
DOI: https://doi.org/10.1111/bcpt.13398
URI: http://hdl.handle.net/10138/318748
Abstract: Abstract In this study, we investigated whether local intramyocardial GATA4 overexpression affects the left ventricular (LV) remodelling process and the importance of phosphorylation at serine-105 (S105) for the actions of GATA4 in an angiotensin II (AngII)-induced hypertension rat model. Adenoviral constructs overexpressing wild type GATA4 or GATA4 mutated at S105 were delivered into the anterior LV free wall. AngII (33.3 µg x kg-1 x h-1) was administered via subcutaneously implanted minipumps. Cardiac function and structure were examined by echocardiography, followed by histological immunostainings of LV sections and gene expression measurements by RT-qPCR. The effects of GATA4 on cultured neonatal rat ventricular fibroblasts were evaluated. In AngII?induced hypertension, GATA4 overexpression repressed fibrotic gene expression, reversed the hypertrophic adult-to-foetal isoform switch of myofibrillar genes and prevented apoptosis, whereas histological fibrosis was not affected. Overexpression of GATA4 mutated at S105 resulted in LV chamber dilatation, cardiac dysfunction and had minor effects on expression of myocardial remodelling genes. Fibrotic gene expression in cardiac fibroblasts was differently affected by overexpression of wild type or mutated GATA4. Our results indicate that GATA4 reduces AngII-induced responses by interfering with pro-fibrotic and hypertrophic gene expressions. GATA4 actions on LV remodelling and fibroblasts are dependent on phosphorylation site S105.
Subject: angiotensin II
fibrosis
hypertension
myocardial remodelling
transcription factor
TRANSCRIPTION FACTOR GATA4
CARDIAC FIBROBLASTS
MYOCARDIAL-INFARCTION
GENE-EXPRESSION
RECEPTOR BLOCKER
NUCLEAR MEDIATOR
HYPERTROPHY
FIBROSIS
KINASE
GROWTH
3111 Biomedicine
Peer reviewed: Yes
Rights: unspecified
Usage restriction: openAccess
Self-archived version: acceptedVersion


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