Up-regulation of NOX1/NADPH oxidase following drug-induced myocardial injury promotes cardiac dysfunction and fibrosis
Up-regulation of NOX1/NADPH oxidase following drug-induced myocardial injury promotes cardiac dysfunction and fibrosis
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DOI：
10.1016/j.freeradbiomed.2018.03.053
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发表时间：
2018-05-20
影响因子：
7.4
通讯作者：
Yabe-Nishimura, Chihiro
中科院分区：
文献类型：
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作者：
Iwata, Kazumi;Matsuno, Kuniharu;Yabe-Nishimura, Chihiro
心脏纤维化是心力衰竭的常见特征，迫切需要阻止纤维化进展的治疗策略。我们在此报道了NOX 1，一种产生超氧化物的NADPH氧化酶的非吞噬亚型，它在药物诱导的心肌损伤模型中促进心脏纤维化。单剂量给予阿霉素（DOX）引起心脏功能障碍，伴随着活性氧的产生增加和心脏中NOX 1 mRNA的显著升高。在Nox 1（-/Y）缺陷的小鼠中，心脏功能保持良好，总体生存率显着提高。然而，血清肌酸激酶水平的升高与野生型小鼠相当（Nox 1（+/Y））。DOX治疗后4d，Nox 1（+/Y）组心肌纤维化程度加重，羟脯氨酸含量增加，基质金属蛋白酶-9活化，而Nox 1（-/Y）组心肌纤维化程度明显减轻。当H9 c2心肌细胞暴露于其匀浆时，观察到NOX 1 mRNA的剂量依赖性增加。TLR 4抑制剂TAK 242可抑制H9 c2细胞中NOX 1 mRNA的表达。当分离的心脏成纤维细胞暴露于H9 c2匀浆，增加的增殖和上调胶原3a 1 mRNA被证明。这些变化显着减弱心脏成纤维细胞暴露于H9 c2窝藏破坏Nox 1的匀浆。这些发现表明，细胞损伤后NOX 1的上调通过加重心脏成纤维细胞的促纤维化反应而促进心脏功能障碍和纤维化。调节NOX 1/NADPH氧化酶信号通路可能是预防心肌损伤后心力衰竭的一种新的治疗策略。
Cardiac fibrosis is a common feature in failing heart and therapeutic strategy to halt the progression of fibrosis is highly needed. We here report on NOX1, a non-phagocytic isoform of superoxide-producing NADPH oxidase, which promotes cardiac fibrosis in a drug-induced myocardial injury model. A single-dose administration of doxorubicin (DOX) elicited cardiac dysfunction accompanied by increased production of reactive oxygen species and marked elevation of NOX1 mRNA in the heart. In mice deficient in Nox1 (Nox1(-/Y)), cardiac functions were well retained and overall survival was significantly improved. However, increased level of serum creatine kinase was equivalent to that of wild-type mice (Nox1(+/Y)). At 4 days after DOX treatment, severe cardiac fibrosis accompanied by increased hydroxyproline content and activation of matrix metalloproteinase-9 was demonstrated in Nox1(+/Y), but it was significantly attenuated in Nox1(-/Y). When H9c2 cardiomyocytes were exposed to their homogenate, a dose-dependent increase in NOX1 mRNA was observed. Up-regulation of NOX1 mRNA in H9c2 co-incubated with their homogenate was abolished in the presence of TAK242, a TLR4 inhibitor. When isolated cardiac fibroblasts were exposed to H9c2 homogenates, increased proliferation and up-regulation of collagen 3a1 mRNA were demonstrated. These changes were significantly attenuated in cardiac fibroblasts exposed to homogenates from H9c2 harboring disrupted Nox1. These findings suggest that up-regulation of NOX1 following cellular damage promotes cardiac dysfunction and fibrosis by aggravating the pro-fibrotic response of cardiac fibroblasts. Modulation of the NOX1/NADPH oxidase signaling pathway may be a novel therapeutic strategy for preventing heart failure after myocardial injury.