State Key Laboratory of Organ Failure Research, National Clinical Research Center of Kidney Disease, Division of Nephrology, Nanfang Hospital, Southern Medical University, Guangzhou, China.
Division of Cardiology, Nanfang Hospital, Southern Medical University, Guangzhou, China.
Sci Rep. 2018 Jun 12;8(1):8996. doi: 10.1038/s41598-018-27064-2.
Activation of the renin-angiotensin system (RAS) is associated with hypertension and heart disease. However, how RAS activation causes cardiac lesions remains elusive. Here we report the involvement of Wnt/β-catenin signaling in this process. In rats with chronic infusion of angiotensin II (Ang II), eight Wnt ligands were induced and β-catenin activated in both cardiomyocytes and cardiac fibroblasts. Blockade of Wnt/β-catenin signaling by small molecule inhibitor ICG-001 restrained Ang II-induced cardiac hypertrophy by normalizing heart size and inhibiting hypertrophic marker genes. ICG-001 also attenuated myocardial fibrosis and inhibited α-smooth muscle actin, fibronectin and collagen I expression. These changes were accompanied by a reduced expression of atrial natriuretic peptide and B-type natriuretic peptide. Interestingly, ICG-001 also lowered blood pressure induced by Ang II. In vitro, Ang II induced multiple Wnt ligands and activated β-catenin in rat primary cardiomyocytes and fibroblasts. ICG-001 inhibited myocyte hypertrophy and Snail1, c-Myc and atrial natriuretic peptide expression, and abolished the fibrogenic effect of Ang II in cardiac fibroblasts. Finally, recombinant Wnt3a was sufficient to induce cardiomyocyte injury and fibroblast activation in vitro. Taken together, these results illustrate an essential role for Wnt/β-catenin in mediating hypertension, cardiac hypertrophy and myocardial fibrosis. Therefore, blockade of this pathway may be a novel strategy for ameliorating hypertensive heart disease.
肾素-血管紧张素系统 (RAS) 的激活与高血压和心脏病有关。然而，RAS 激活如何导致心脏病变仍不清楚。在这里，我们报告了 Wnt/β-连环蛋白信号通路在此过程中的参与。在接受血管紧张素 II (Ang II) 慢性输注的大鼠中，八种 Wnt 配体在心肌细胞和心脏成纤维细胞中均被诱导，β-连环蛋白被激活。小分子抑制剂 ICG-001 阻断 Wnt/β-连环蛋白信号通路可通过使心脏大小正常化并抑制肥大标志物基因来抑制 Ang II 诱导的心肌肥大。ICG-001 还减轻了心肌纤维化并抑制了α-平滑肌肌动蛋白、纤维连接蛋白和胶原 I 的表达。这些变化伴随着心房利钠肽和 B 型利钠肽表达的减少。有趣的是，ICG-001 还降低了 Ang II 引起的血压。在体外，Ang II 诱导大鼠原代心肌细胞和成纤维细胞中多种 Wnt 配体并激活β-连环蛋白。ICG-001 抑制心肌细胞肥大和 Snail1、c-Myc 和心房利钠肽的表达，并消除 Ang II 在心脏成纤维细胞中的纤维生成作用。最后，重组 Wnt3a 足以在体外诱导心肌细胞损伤和成纤维细胞激活。总之，这些结果表明 Wnt/β-连环蛋白在介导高血压、心肌肥大和心肌纤维化方面起着重要作用。因此，阻断该通路可能是改善高血压性心脏病的一种新策略。
