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Mitogen‐activated protein kinase p38 target regenerating islet‐derived 3 γ expression is upregulated in cardiac inflammatory response in the rat heart
Author(s) -
Säkkinen Hanna,
Aro Jani,
Kaikkonen Leena,
Ohukainen Pauli,
Näpänkangas Juha,
Tokola Heikki,
Ruskoaho Heikki,
Rysä Jaana
Publication year - 2016
Publication title -
physiological reports
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 0.918
H-Index - 39
ISSN - 2051-817X
DOI - 10.14814/phy2.12996
Subject(s) - downregulation and upregulation , protein kinase a , p38 mitogen activated protein kinases , biology , mapk/erk pathway , gene expression , angiotensin ii , mitogen activated protein kinase , kinase , microbiology and biotechnology , medicine , endocrinology , gene , biochemistry , blood pressure
Regenerating islet‐derived 3 γ (Reg3 γ ) 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 Reg3 γ expression in cardiac inflammatory conditions. Reg3 γ expression was studied in experimental rat models of myocardial infarction ( MI ) and pressure overload in vivo. For cell culture studies neonatal rat cardiac myocytes ( NRCM s) were used. In addition, adenovirus‐mediated gene transfer of upstream mitogen‐activated protein kinase ( MAPK ) kinase 3b and p38 α MAPK in vivo and in vitro was performed. Reg3 γ 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 Reg3 γ mRNA levels from 6 h to 2 weeks. Immunohistochemistry revealed that the Ang II ‐induced expression of Reg3 γ 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 Reg3 γ mRNA levels in NRCM s. SB 203580, a selective p38 MAPK inhibitor, markedly attenuated LPS and mechanical stretch‐induced upregulation of Reg3 γ gene expression. Moreover, combined overexpression of MKK 3bE and WT p38 α increased Reg3 γ gene expression in cultured cardiomyocytes in vitro and in the rat heart in vivo. Our study shows that cardiac stress activates Reg3 γ expression and p38 MAPK is an upstream regulator of Reg3 γ gene expression in heart. Altogether our data suggest Reg3 γ is associated with cardiac inflammatory signaling.