Missinato Maria A, Saydmohammed Manush, Zuppo Daniel A, Rao Krithika S, Opie Graham W, Kühn Bernhard, Tsang Michael
Department of Developmental Biology, University of Pittsburgh, School of Medicine, Pittsburgh, PA 15213, USA.
Pediatric Institute for Heart Regeneration and Therapeutics (I-HRT), Richard King Mellon Foundation Institute for Pediatric Research and Division of Cardiology, Children's Hospital of Pittsburgh of UPMC and Department of Pediatrics, University of Pittsburgh, Pittsburgh, PA 15224, USA.
Development. 2018 Mar 6;145(5):dev157206. doi: 10.1242/dev.157206.
Zebrafish regenerate cardiac tissue through proliferation of pre-existing cardiomyocytes and neovascularization. Secreted growth factors such as FGFs, IGF, PDGFs and Neuregulin play essential roles in stimulating cardiomyocyte proliferation. These factors activate the Ras/MAPK pathway, which is tightly controlled by the feedback attenuator Dual specificity phosphatase 6 (Dusp6), an ERK phosphatase. Here, we show that suppressing Dusp6 function enhances cardiac regeneration. Inactivation of Dusp6 by small molecules or by gene inactivation increased cardiomyocyte proliferation, coronary angiogenesis, and reduced fibrosis after ventricular resection. Inhibition of Erbb or PDGF receptor signaling suppressed cardiac regeneration in wild-type zebrafish, but had a milder effect on regeneration in mutants. Moreover, in rat primary cardiomyocytes, NRG1-stimulated proliferation can be enhanced upon chemical inhibition of Dusp6 with BCI. Our results suggest that Dusp6 attenuates Ras/MAPK signaling during regeneration and that suppressing Dusp6 can enhance cardiac repair.
斑马鱼通过已有的心肌细胞增殖和新血管形成来再生心脏组织。分泌的生长因子如成纤维细胞生长因子（FGFs）、胰岛素样生长因子（IGF）、血小板衍生生长因子（PDGFs）和神经调节蛋白在刺激心肌细胞增殖中起关键作用。这些因子激活Ras/丝裂原活化蛋白激酶（MAPK）信号通路，该通路由反馈衰减器双特异性磷酸酶6（Dusp6，一种细胞外信号调节激酶（ERK）磷酸酶）严格控制。在此，我们表明抑制Dusp6功能可增强心脏再生。通过小分子或基因失活使Dusp6失活可增加心肌细胞增殖、冠状动脉血管生成，并减少心室切除术后的纤维化。抑制Erbb或血小板衍生生长因子受体信号传导可抑制野生型斑马鱼的心脏再生，但对突变体的再生影响较小。此外，在大鼠原代心肌细胞中，用BCI化学抑制Dusp6可增强神经调节蛋白1（NRG1）刺激的增殖。我们的结果表明，Dusp6在再生过程中减弱Ras/MAPK信号传导，抑制Dusp6可增强心脏修复。
