RhoE Fine-Tunes Inflammatory Response in Myocardial Infarction
RhoE Fine-Tunes Inflammatory Response in Myocardial Infarction
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RhoE 微调心肌梗塞的炎症反应
DOI：
10.1161/circulationaha.118.033700
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发表时间：
2019-02-26
期刊：
影响因子：
37.8
通讯作者：
Chang, Jiang
中科院分区：
文献类型：
--
作者：
Dai, Yuan;Song, Jiangping;Chang, Jiang
背景资料：心肌梗死（MI）后的炎症反应是心脏愈合所必需的，而过度和长期的炎症会延长梗死并促进不良的心脏重塑。了解这些严格控制的炎症过程的机制对MI后的恢复和治疗有重要影响。在这里，我们揭示了小GTTRhoE在MI后恢复中的关键作用及其临床意义。研究方法：使用了三种遗传小鼠系：全局Rhoe敲除小鼠、心肌细胞特异性Rhoe杂合小鼠和心肌细胞特异性Rhoe过表达小鼠。一组分子信号实验，包括双分子荧光互补，免疫沉淀，电泳迁移率变动分析，和mRNA微阵列分析，进行。行左前降支永久性结扎，然后在MI后第一周评估心功能、炎症和存活率。最后，我们研究了RhoE在MI患者心脏中的表达水平与患者预后的相关性。结果：RhoE缺乏可引起小鼠心脏一组促炎基因表达。具有心肌细胞特异性单倍性不足的小鼠在MI后表现出过度的炎症反应和有害的心脏功能。在突变心脏和分离的心肌细胞中检测到核因子- B活性的显著增加。我们进一步发现，RhoE的表达上调响应MI。在机制上，RhoE与p65和p50在胞质溶胶中单独相互作用，并阻断它们的核转位。Rhoe还占据p65的二聚化结构域，随后破坏p65和p50之间的异二聚化。心脏RhoE过表达抑制核因子-B活性，抑制MI后炎症，并改善心脏功能和存活率。因此，我们发现RhoE在MI患者心脏中的表达水平升高，RhoE表达水平高的患者在心功能恢复方面表现出更好的预后。结论：本研究揭示RhoE作为一种新的微调因子调节MI诱导的炎症反应，促进受损心脏的恢复。RhoE可能作为一种新的潜在的生物标志物，用于评估MI患者的预后。RhoE的调控可能成为心肌梗死及其他炎症性疾病的潜在治疗方法。
Background: Inflammatory response after myocardial infarction (MI) is essential for cardiac healing, whereas excessive and prolonged inflammation extends the infarction and promotes adverse cardiac remodeling. Understanding the mechanistic insight of these tightly controlled inflammatory processes has a significant impact on post-MI recovery and therapy. Here, we uncover the critical role of small GTPase RhoE in post-MI recovery and its clinical implication. Methods: Three genetic mouse lines are used: global RhoE knockout, cardiomyocyte-specific RhoE heterozygous, and cardiomyocyte-specific RhoE overexpression mice. A set of molecular signaling experiments, including bimolecular fluorescence complementation, immunoprecipitation, electrophoretic mobility shift assay, and mRNA microarray analysis, were conducted. Permanent ligation of the left anterior descending artery was performed, followed by the assessments of cardiac function, inflammation, and survival in the first week after MI. Finally, we examined the correlation of the expression levels of RhoE in MI patient heart and patient prognosis. Results: RhoE deficiency turns on a group of proinflammatory gene expressions in mouse heart. Mice with cardiomyocyte-specific haploinsufficiency exhibit excessive inflammatory response with deleterious cardiac function after MI. A profound increase in nuclear factor-&kgr;B activity is detected in the mutant heart and the isolated cardiomyocytes. We further find that the expression of RhoE is upregulated in response to MI. Mechanistically, RhoE interacts with p65 and p50 individually in cytosol and blocks their nuclear translocation. RhoE also occupies the dimerization domain of p65 and subsequently disrupts the heterodimerization between p65 and p50. Cardiac RhoE overexpression inhibits nuclear factor-&kgr;B activity, restrains post-MI inflammation, and improves cardiac function and survival. Consistently, we find that the expression level of RhoE is elevated in the heart of patients with MI and that the patients with a higher expression level of RhoE exhibit a better prognosis in cardiac function recovery. Conclusions: The study uncovers RhoE as a new fine-tuning factor modulating MI-induced inflammation and promoting injured heart recovery. RhoE may serve as a new potential biomarker for the assessment of MI patient prognosis. Manipulation of RhoE could be as a potential therapeutic approach for MI and other inflammatory diseases.