Center for Translational Cancer Research, Texas A&M University Institute of Biosciences and Technology, Houston (Y.D., W.L., T.Y., X.L., W.L., K.C.A., J.C.).
Department of Cardiac Surgery, State Key Laboratory of Cardiovascular Disease, Fuwai Hospital, National Center for Cardiovascular Diseases, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing, China (J.S., X.W., S.L.).
Circulation. 2019 Feb 26;139(9):1185-1198. doi: 10.1161/CIRCULATIONAHA.118.033700.
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.
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.
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-κB 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-κB 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.
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.
心肌梗死后的炎症反应对心脏愈合至关重要，而过度和持续的炎症会扩大梗死面积并促进不良的心脏重构。了解这些严格控制的炎症过程的机制见解，对心肌梗死后的恢复和治疗有重要影响。在这里，我们揭示了小 GTPase RhoE 在心肌梗死后恢复中的关键作用及其临床意义。
使用三种遗传小鼠品系：全局 RhoE 敲除、心肌细胞特异性 RhoE 杂合子和心肌细胞特异性 RhoE 过表达小鼠。进行了一系列分子信号实验，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。通过左前降支永久性结扎，评估心肌梗死后第 1 周的心脏功能、炎症和存活情况。最后，我们检测了 RhoE 在心肌梗死患者心脏中的表达水平与患者预后的相关性。
RhoE 缺失会使小鼠心脏中的一组促炎基因表达上调。心肌细胞特异性半合子缺陷小鼠在心肌梗死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-κB 活性显著增加。我们进一步发现，RhoE 的表达在心肌梗死后上调。机制上，RhoE 在细胞质中分别与 p65 和 p50 相互作用，并阻止它们的核转位。RhoE 还占据 p65 的二聚化结构域，从而破坏 p65 和 p50 之间的异二聚化。心脏 RhoE 过表达抑制核因子-κB 活性，抑制心肌梗死后炎症，改善心脏功能和存活。一致地，我们发现 RhoE 在心肌梗死患者的心脏中表达上调，并且 RhoE 表达水平较高的患者在心脏功能恢复方面预后更好。
该研究揭示了 RhoE 作为一种新的微调因子，调节心肌梗死后的炎症反应，促进受损心脏恢复。RhoE 可作为评估心肌梗死患者预后的新的潜在生物标志物。RhoE 的调控可能成为心肌梗死和其他炎症性疾病的潜在治疗方法。
