title: Mitogen-activated protein kinase p38 target regenerating islet-derived 3γ expression is upregulated in cardiac inflammatory response in the rat heart.
abstract: 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.
authors: Research Unit of Biomedicine, Pharmacology and Toxicology, University of Oulu, Oulu, Finland.
authors: Hanna
authors: H
authors: Säkkinen
authors: Research Unit of Biomedicine, Pharmacology and Toxicology, University of Oulu, Oulu, Finland.
authors: Jani
authors: J
authors: Aro
authors: Research Unit of Biomedicine, Pharmacology and Toxicology, University of Oulu, Oulu, Finland.
authors: Leena
authors: L
authors: Kaikkonen
authors: Research Unit of Biomedicine, Pharmacology and Toxicology, University of Oulu, Oulu, Finland.
authors: Pauli
authors: P
authors: Ohukainen
authors: Department of Pathology, Cancer Research and Translational Medicine Research Unit, University of Oulu and Oulu University Hospital, Oulu, Finland.
authors: Juha
authors: J
authors: Näpänkangas
authors: Department of Pathology, Cancer Research and Translational Medicine Research Unit, University of Oulu and Oulu University Hospital, Oulu, Finland.
authors: Heikki
authors: H
authors: Tokola
authors: Research Unit of Biomedicine, Pharmacology and Toxicology, University of Oulu, Oulu, Finland heikki.ruskoaho@helsinki.fi.|Division of Pharmacology and Pharmacotherapy, University of Helsinki, Helsinki, Finland.
authors: Heikki
authors: H
authors: Ruskoaho
authors: Research Unit of Biomedicine, Pharmacology and Toxicology, University of Oulu, Oulu, Finland.|School of Pharmacy, University of Eastern Finland, Kuopio, Finland.
authors: Jaana
authors: J
authors: Rysä
mesh_terms: D000818:Animals; D006352:Heart Ventricles / Q000378:metabolism*; D008297:Male; D020928:Mitogen-Activated Protein Kinases / Q000378:metabolism*; D009203:Myocardial Infarction / Q000378:metabolism*; D009206:Myocardium / Q000473:pathology*; D032383:Myocytes, Cardiac / Q000378:metabolism; D000073718:Pancreatitis-Associated Proteins; D011506:Proteins / Q000378:metabolism; D051381:Rats; D017207:Rats, Sprague-Dawley; D013314:Stress, Mechanical; D048051:p38 Mitogen-Activated Protein Kinases / Q000378:metabolism*
chemical_list: D000073718:Pancreatitis-Associated Proteins; D011506:Proteins; C490255:Reg3g protein, mouse; D020928:Mitogen-Activated Protein Kinases; D048051:p38 Mitogen-Activated Protein Kinases
keywords: Cardiac hypertrophy; inflammatory response; myocardial infarction; pressure overload