MicroRNA-24 Regulates Vascularity After Myocardial Infarction

被引：477

作者：

Fiedler, Jan ^{[1
]}

Jazbutyte, Virginija ^{[1
]}

Kirchmaier, Bettina C. ^{[4
,5
,6
]}

Gupta, Shashi K. ^{[1
]}

Lorenzen, Johan ^{[1
]}

Hartmann, Dorothee ^{[1
]}

Galuppo, Paolo ^{[2
]}

Kneitz, Susanne ^{[7
]}

Pena, John T. G. ^{[8
]}

Sohn-Lee, Cherin ^{[8
]}

Loyer, Xavier ^{[9
]}

Soutschek, Juergen ^{[10
]}

Brand, Thomas ^{[6
,11
]}

Tuschl, Thomas ^{[8
]}

Heineke, Joerg ^{[2
]}

Martin, Ulrich ^{[3
]}

Schulte-Merker, Stefan ^{[4
,5
]}

Ertl, Georg ^{[12
]}

Engelhardt, Stefan ^{[9
]}

Bauersachs, Johann ^{[2
]}

Thum, Thomas ^{[1
,13
]}

机构：

[1] Hannover Med Sch, IMTTS, D-30625 Hannover, Germany

[2] Hannover Med Sch, Dept Cardiol & Angiol, D-30625 Hannover, Germany

[3] Hannover Med Sch, Leibniz Res Labs Biotechnol & Artificial Organs, D-30625 Hannover, Germany

[4] Hubrecht Inst KNAW, Utrecht, Netherlands

[5] Univ Med Ctr, Utrecht, Netherlands

[6] Univ Wurzburg, Bioctr, Wurzburg, Germany

[7] Univ Wurzburg, Interdisciplinary Ctr Clin Res, Microarray Core Facil, Wurzburg, Germany

[8] Rockefeller Univ, Lab RNA Mol Biol, New York, NY 10021 USA

[9] Tech Univ Munich, Inst Pharmacol & Toxicol, D-8000 Munich, Germany

[10] Regulus Therapeut, San Diego, CA USA

[11] Univ London Imperial Coll Sci Technol & Med, Natl Heart & Lung Inst, London, England

[12] Univ Hosp Wuerzburg, Dept Internal Med 1, Wurzburg, Germany

[13] IRCCS San Raffaele, Ctr Clin & Basic Res, Rome, Italy

来源：

CIRCULATION | 2011年 / 124卷 / 06期

关键词：

myocardial infarction; microRNAs; angiogenesis; antagomir; gene expression; heart failure; HUMAN ENDOTHELIAL-CELLS; HEART-FAILURE; GENE-EXPRESSION; CONTROLS ANGIOGENESIS; CARDIAC-HYPERTROPHY; DOWN-REGULATION; KAPPA-B; ACTIVATION; NEOVASCULARIZATION; ZEBRAFISH;

D O I：

10.1161/CIRCULATIONAHA.111.039008

中图分类号：

R5 [内科学];

学科分类号：

100201 [内科学];

摘要：

Background-Myocardial infarction leads to cardiac remodeling and development of heart failure. Insufficient myocardial capillary density after myocardial infarction has been identified as a critical event in this process, although the underlying mechanisms of cardiac angiogenesis are mechanistically not well understood. Methods and Results-Here, we show that the small noncoding RNA microRNA-24 (miR-24) is enriched in cardiac endothelial cells and considerably upregulated after cardiac ischemia. MiR-24 induces endothelial cell apoptosis, abolishes endothelial capillary network formation on Matrigel, and inhibits cell sprouting from endothelial spheroids. These effects are mediated through targeting of the endothelium-enriched transcription factor GATA2 and the p21-activated kinase PAK4, which were identified by bioinformatic predictions and validated by luciferase gene reporter assays. Respective downstream signaling cascades involving phosphorylated BAD (Bcl-XL/Bcl-2-associated death promoter) and Sirtuin1 were identified by transcriptome, protein arrays, and chromatin immunoprecipitation analyses. Overexpression of miR-24 or silencing of its targets significantly impaired angiogenesis in zebrafish embryos. Blocking of endothelial miR-24 limited myocardial infarct size of mice via prevention of endothelial apoptosis and enhancement of vascularity, which led to preserved cardiac function and survival. Conclusions-Our findings indicate that miR-24 acts as a critical regulator of endothelial cell apoptosis and angiogenesis and is suitable for therapeutic intervention in the setting of ischemic heart disease. (Circulation. 2011; 124: 720-730.)

引用

页码：720 / U178

页数：29

共 57 条

[1]

The functions of animal microRNAs [J].