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

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 (NRCMs) 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 NRCMs. SB203580, a selective p38 MAPK inhibitor, markedly attenuated LPS and mechanical stretch‐induced upregulation of Reg3 γ gene expression. Moreover, combined overexpression of MKK3bE 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.