RhoE Fine-Tunes Inflammatory Response in Myocardial Infarction

被引:52
|
作者
Dai, Yuan [2 ]
Song, Jiangping [3 ,4 ]
Li, Wenjiao [2 ]
Yang, Tingli [2 ]
Yue, Xiaojing [5 ]
Lin, Xi [1 ]
Yang, Xiangsheng [6 ]
Luo, Weijia [2 ]
Guo, Junli [7 ]
Wang, Xin [3 ,4 ]
Lai, Songqing [3 ,4 ]
Andrade, Kelsey C. [2 ]
Chang, Jiang [2 ]
机构
[1] Texas A&M Univ, Coll Med, Inst Biosci & Technol, 2121 W Holcombe Blvd, Houston, TX 77030 USA
[2] Texas A&M Univ, Ctr Translat Canc Res, Inst Biosci & Technol, Houston, TX USA
[3] Chinese Acad Med Sci, Natl Ctr Cardiovasc Dis, Fuwai Hosp, Dept Cardiac Surg,State Key Lab Cardiovasc Dis, Beijing 100037, Peoples R China
[4] Peking Union Med Coll, Beijing 100037, Peoples R China
[5] Southern Med Univ, Nanfang Hosp, Dept Obstet & Gynecol, Guangzhou, Guangdong, Peoples R China
[6] Guangzhou Biotron Technol Co Ltd, Guangzhou, Guangdong, Peoples R China
[7] Hainan Med Univ, Minist Educ, Key Lab Trop Dis & Translat Med, Cardiovasc Dis & Res Inst,Affiliated Hosp 1, Haikou, Hainan, Peoples R China
基金
中国国家自然科学基金;
关键词
inflammation; myocardial infarction; NF-kappa B; Rho-GTP-binding proteins; NF-KAPPA-B; GENETIC DELETION; DOWN-REGULATION; UP-REGULATION; MOUSE HEART; ROCK-I; PHOSPHORYLATION; ACTIVATION; REPAIR; EXPRESSION;
D O I
10.1161/CIRCULATIONAHA.118.033700
中图分类号
R5 [内科学];
学科分类号
1002 ; 100201 ;
摘要
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-kappa 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-kappa 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.
引用
收藏
页码:1185 / 1198
页数:14
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