Jurado Acosta, A, Rysä, J, Szabo, Z, Moilanen, A‐M, Serpi, R, Ruskoaho, H. Phosphorylation of GATA4 at serine 105 is required for left ventricular remodelling process in angiotensin II‐induced hypertension in rats. Basic Clin Pharmacol Toxicol. 2020; 127: 178– 195. https://doi.org/10.1111/bcpt.13398
Phosphorylation of GATA4 at serine 105 is required for left ventricular remodelling process in angiotensin II‐induced hypertension in rats
|Author:||Jurado Acosta, Alicia1; Rysä, Jaana2; Szabo, Zoltan1;|
1Pharmacology and Toxicology, Biomedicine Research Unit, Faculty of Medicine, University of Oulu, Oulu, Finland
2School of Pharmacy, Faculty of Health Sciences, University of Eastern Finland, Kuopio, Finland
3Cancer and Translational Medicine Research Unit, University of Oulu, Oulu, Finland
4Oulu University Hospital and Medical Research Center Oulu, Oulu, Finland
5Biocenter Oulu, Faculty of Biochemistry and Molecular Medicine, Oulu Center for Cell‐Matrix Research, University of Oulu, Oulu, Finland
6Drug Research Program, Division of Pharmacology and Pharmacotherapy, Faculty of Pharmacy, University of Helsinki, Helsinki, Finland
|Online Access:||PDF Full Text (PDF, 2.2 MB)|
|Persistent link:|| http://urn.fi/urn:nbn:fi-fe2020103088868
John Wiley & Sons,
|Publish Date:|| 2020-10-30
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/kg/h) 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.
Basic & clinical pharmacology & toxicology
|Pages:||178 - 195|
|Type of Publication:||
A1 Journal article – refereed
|Field of Science:||
Sydäntutkimussäätiö; Academy of Finland, Grant/Award Number: 266661 and 276747; Tekes, Grant/Award Number: 40395/13; Sigrid Juséliuksen Säätiö; Jenny ja Antti Wihurin Rahasto.
© 2020 The Authors. Basic & Clinical Pharmacology & Toxicology published by John Wiley & Sons Ltd on behalf of Nordic Association for the Publication of BCPT (former Nordic Pharmacological Society). This is an open access article under the terms of the Creative Commons Attribution‐NonCommercial License, which permits use, distribution and reproduction in any medium, provided the original work is properly cited and is not used for commercial purposes.