Somanna Naveen K, Valente Anthony J, Krenz Maike, Fay William P, Delafontaine Patrice, Chandrasekar Bysani
Microbiology, Tulane University School of Medicine, New Orleans, Louisiana.
Medicine, University of Texas Health Science Center, San Antonio, Texas.
J Cell Physiol. 2016 May;231(5):1130-41. doi: 10.1002/jcp.25210. Epub 2015 Oct 19.
Both oxidative stress and inflammation contribute to chronic hypertension-induced myocardial fibrosis and adverse cardiac remodeling. Here we investigated whether angiotensin (Ang)-II-induced fibroblast proliferation and migration are NADPH oxidase (Nox) 4/ROS and IL-18 dependent. Our results show that the potent induction of mouse cardiac fibroblast (CF) proliferation and migration by Ang-II is markedly attenuated by Nox4 knockdown and the Nox inhibitor DPI. Further, Nox4 knockdown and DPI pre-treatment attenuated Ang-II-induced IL-18, IL-18Rα and collagen expression, and MMP9 and LOX activation. While neutralization of IL-18 blunted Ang-II-induced CF proliferation and migration, knockdown of MMP9 attenuated CF migration. The antioxidant NAC and the cell-permeable SOD mimetics Tempol, MnTBAP, and MnTMPyP attenuated oxidative stress and inhibited CF proliferation and migration. The Nox1/Nox4 dual inhibitor GKT137831 also blunted Ang-II-induced H2 O2 production and CF proliferation and migration. Further, AT1 bound Nox4, and Ang-II enhanced their physical association. Notably, GKT137831 attenuated the AT1/Nox4 interaction. These results indicate that Ang-II induces CF proliferation and migration in part via Nox4/ROS-dependent IL-18 induction and MMP9 activation, and may involve AT1/Nox4 physical association. Thus, either (i) neutralizing IL-18, (ii) blocking AT1/Nox4 interaction or (iii) use of the Nox1/Nox4 inhibitor GKT137831 may have therapeutic potential in chronic hypertension-induced adverse cardiac remodeling.
氧化应激和炎症均会导致慢性高血压引起的心肌纤维化和不良心脏重塑。在此，我们研究了血管紧张素（Ang）-II诱导的成纤维细胞增殖和迁移是否依赖于NADPH氧化酶（Nox）4/活性氧（ROS）和白细胞介素-18（IL-18）。我们的结果表明，Nox4基因敲低和Nox抑制剂二苯基碘鎓（DPI）可显著减弱Ang-II对小鼠心脏成纤维细胞（CF）增殖和迁移的强力诱导作用。此外，Nox4基因敲低和DPI预处理可减弱Ang-II诱导的IL-18、IL-18受体α（IL-18Rα）和胶原蛋白表达，以及基质金属蛋白酶9（MMP9）和赖氨氧化酶（LOX）的激活。虽然中和IL-18可减弱Ang-II诱导的CF增殖和迁移，但敲低MMP9可减弱CF迁移。抗氧化剂N-乙酰半胱氨酸（NAC）以及可透过细胞的超氧化物歧化酶（SOD）模拟物Tempol、四（4-N-甲基吡啶基）卟啉锰（MnTBAP）和四（1-甲基-4-吡啶基）卟啉锰（MnTMPyP）可减轻氧化应激并抑制CF增殖和迁移。Nox1/Nox4双重抑制剂GKT137831也可减弱Ang-II诱导的过氧化氢（H2O2）生成以及CF增殖和迁移。此外，血管紧张素II 1型受体（AT1）与Nox4结合，且Ang-II增强了它们之间的物理相互作用。值得注意的是，GKT137831可减弱AT1/Nox4相互作用。这些结果表明，Ang-II部分通过Nox4/ROS依赖性的IL-18诱导和MMP9激活来诱导CF增殖和迁移，并且可能涉及AT1/Nox4物理相互作用。因此，（i）中和IL-18、（ii）阻断AT1/Nox4相互作用或（iii）使用Nox1/Nox4抑制剂GKT137831可能对慢性高血压引起的不良心脏重塑具有治疗潜力。
