University of Oulu

Säkkinen, H., Aro, J., Kaikkonen, L., Ohukainen, P., Näpänkangas, J., Tokola, H., Ruskoaho, H., Rysä, J.. Mitogen-activated protein kinase p38 target regenerating islet-derived 3γ expression is upregulated in cardiac inflammatory response in the rat heart. Physiol Rep, 4 ( 20), 2016, e12996, doi: 10.14814/phy2.12996

Mitogen-activated protein kinase p38 target regenerating islet-derived 3γ expression is upregulated in cardiac inflammatory response in the rat heart

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Author: Säkkinen, Hanna1; Aro, Jani1; Kaikkonen, Leena1;
Organizations: 1Research Unit of Biomedicine, Pharmacology and Toxicology, University of Oulu, Oulu, Finland
2Department of Pathology, Cancer Research and Translational Medicine Research Unit, University of Oulu and Oulu University Hospital, Oulu, Finland
3Division of Pharmacology and Pharmacotherapy, University of Helsinki, Helsinki, Finland
4School of Pharmacy, University of Eastern Finland, Kuopio, Finland
Format: article
Version: published version
Access: open
Online Access: PDF Full Text (PDF, 1.8 MB)
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Language: English
Published: John Wiley & Sons, 2016
Publish Date: 2023-04-20


Regenerating islet-derived 3γ (Reg3γ) is a multifunctional protein, associated with various tissue injuries and inflammatory states. Since chronic inflammation is characteristics also for heart failure, the aim of this study was to characterize Reg3γ expression in cardiac inflammatory conditions. Reg3γ expression was studied in experimental rat models of myocardial infarction (MI) and pressure overload in vivo. For cell culture studies neonatal rat cardiac myocytes (NRCMs) were used. In addition, adenovirus-mediated gene transfer of upstream mitogen-activated protein kinase (MAPK) kinase 3b and p38α MAPK in vivo and in vitro was performed. Reg3γ mRNA (12.8-fold, P < 0.01) and protein (5.8-fold, P < 0.001) levels were upregulated during the postinfarction remodeling at day 1 after MI, and angiotensin II (Ang II) markedly increased Reg3γ mRNA levels from 6 h to 2 weeks. Immunohistochemistry revealed that the Ang II-induced expression of Reg3γ was localized into the cardiac fibroblasts and myofibroblasts of the proliferating connective tissue in the heart. Stretching and treatments with endothelin-1, lipopolysaccharide (LPS), and fibroblast growth factor-1 increased Reg3γ mRNA levels in NRCMs. SB203580, a selective p38 MAPK inhibitor, markedly attenuated LPS and mechanical stretch-induced upregulation of Reg3γ gene expression. Moreover, combined overexpression of MKK3bE and WT p38α increased Reg3γ gene expression in cultured cardiomyocytes in vitro and in the rat heart in vivo. Our study shows that cardiac stress activates Reg3γ expression and p38 MAPK is an upstream regulator of Reg3γ gene expression in heart. Altogether our data suggest Reg3γ is associated with cardiac inflammatory signaling.

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Series: Physiological reports
ISSN: 2051-817X
ISSN-E: 2051-817X
ISSN-L: 2051-817X
Volume: 4
Issue: 20
Article number: e12996
DOI: 10.14814/phy2.12996
Type of Publication: A1 Journal article – refereed
Field of Science: 3111 Biomedicine
Funding: This work was supported by grants from the Academy of Finland (Centre of Excellence) funding (H.R.) and grants 266661 (H.R.) and 276747 (J.R.), Sigrid Juselius Foundation, Finnish Foundation for Cardiovascular Research, Paavo Nurmi Foundation, and Aarne Koskelo Foundation.
Academy of Finland Grant Number: 266661
Detailed Information: 266661 (Academy of Finland Funding decision)
276747 (Academy of Finland Funding decision)
Copyright information: © 2016 The Authors. Physiological Reports published by Wiley Periodicals, Inc. on behalf of the American Physiological Society and The Physiological Society. This is an open access article under the terms of the Creative Commons Attribution License, which permits use, distribution and reproduction in any medium, provided the original work is properly cited.