Säkkinen Hanna, Aro Jani, Kaikkonen Leena, Ohukainen Pauli, Näpänkangas Juha, Tokola Heikki, Ruskoaho Heikki, Rysä Jaana
Research Unit of Biomedicine, Pharmacology and Toxicology, University of Oulu, Oulu, Finland.
Department of Pathology, Cancer Research and Translational Medicine Research Unit, University of Oulu and Oulu University Hospital, Oulu, Finland.
Physiol Rep. 2016 Oct;4(20). doi: 10.14814/phy2.12996. Epub 2016 Oct 24.
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.
再生胰岛衍生蛋白3γ（Reg3γ）是一种多功能蛋白，与多种组织损伤和炎症状态相关。由于慢性炎症也是心力衰竭的特征，本研究旨在描述Reg3γ在心脏炎症状态下的表达特征。在体内的心肌梗死（MI）和压力超负荷实验大鼠模型中研究了Reg3γ的表达。细胞培养研究使用新生大鼠心肌细胞（NRCMs）。此外，还在体内和体外进行了腺病毒介导的上游丝裂原活化蛋白激酶（MAPK）激酶3b和p38α MAPK的基因转移。MI后第1天梗死后期重塑期间，Reg3γ mRNA水平上调了12.8倍（P < 0.01），蛋白水平上调了5.8倍（P < 0.001），并且血管紧张素II（Ang II）在6小时至2周内显著增加了Reg3γ mRNA水平。免疫组织化学显示，Ang II诱导的Reg3γ表达定位于心脏增殖结缔组织的心脏成纤维细胞和肌成纤维细胞中。拉伸以及用内皮素-1、脂多糖（LPS）和成纤维细胞生长因子-1处理可增加NRCMs中Reg3γ mRNA水平。选择性p38 MAPK抑制剂SB203580显著减弱了LPS和机械拉伸诱导的Reg3γ基因表达上调。此外，MKK3bE和野生型p38α的联合过表达在体外培养的心肌细胞和体内大鼠心脏中增加了Reg3γ基因表达。我们的研究表明，心脏应激激活Reg3γ表达，并且p38 MAPK是心脏中Reg3γ基因表达的上游调节因子。总之，我们的数据表明Reg3γ与心脏炎症信号传导相关。
