elevated mir-499 levels blunt the cardiac stress responsemir - 499水平升高的心脏压力反应.pdfVIP

Elevated miR-499 Levels Blunt the Cardiac Stress Response 1,2 1 3 1,4,5 Joseph T. C. Shieh , Yu Huang , Jacqueline Gilmore , Deepak Srivastava * 1 Gladstone Institute of Cardiovascular Disease, San Francisco, California, United States of America, 2 Division of Medical Genetics, Department of Pediatrics, University of California San Francisco, San Francisco, California, United States of America, 3 School of Medicine, University of California San Francisco, San Francisco, California, United States of America, 4 Division of Pediatric Cardiology, Department of Pediatrics, University of California San Francisco, San Francisco, California, United States of America, 5 Department of Biochemistry and Biophysics, University of California San Francisco, San Francisco, California, United States of America Abstract Background: The heart responds to myriad stresses by well-described transcriptional responses that involve long-term changes in gene expression as well as more immediate, transient adaptations. MicroRNAs quantitatively regulate mRNAs and thus may affect the cardiac transcriptional output and cardiac function. Here we investigate miR-499, a microRNA embedded within a ventricular-specific myosin heavy chain gene, which is expressed in heart and skeletal muscle. Methodology/Principal Findings: We assessed miR-499 expression in human tissue to confirm its potential relevance to human cardiac gene regulation. Using a transgenic mouse model, we found that elevated miR-499 levels caused cellular hypertrophy and cardiac dysfunction in a dose-dependent manner. Global gene expression profiling revealed altered levels of the immediate early stress response genes (Egr1, Egr2 and Fos), ß-myosin heavy chain (Myh7), and skeletal mus