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THE ROLE OF MICRORNA-1 AND MICRORNA-21 IN THE DEVELOPMENT OF CARDIAC HYPERTROPHY

by
Danish H. Sayed
Cell Biology and Molecular Medicine

M.B.B.S, 1998, Dr. P.D.M. Medical College, Amravati, India
M.S., 2003, Montclair State University

Thesis Advisor: Maha Abdellatif, M.D., Ph.D.
Associate Professor
Cell Biology and Molecular Medicine

Tuesday, April 15, 2008
10:00 a.m.

Cell Biology and Molecular Medicine
MSB G-Level
Conference Room

Tuesday, April 15, 2008
10:00 a.m.


Abstract

Post-transcriptional gene regulation by microRNAs plays a critical role in modulating all cell processes from development, differentiation to cell survival. The role of miRNA in heart is still limited with previous studies only identifying and characterizing the involvement of miRNA-1 during development. On the other hand studied extensively in cancer, miRNA dysregulation suggest an important oncogenic property and function in carcinogenesis. Our hypothesis was that miRNAs are regulated during the cardiac hypertrophy and play an essential role in the development and maintenance of hypertrophy.
We identified miRNAs that are differentially regulated during different stages of hypertrophy in mice hearts subjected to Transaortic Constriction (TAC). Of the miRNAs regulated, miRNA-1 and miRNA-21 stood out from the rest with opposing differential expression and levels. MiRNA-1, with very high endogenous levels, decreased before actual increase in heart/body weight, while miRNA-21 with comparatively low starting levels gradually increased by ~8 folds during cardiac hypertrophy, returning back to normal levels during decompensation. In-silico predicted targets of miRNA-1 include a cluster of pro-hypertrophic genes that independently have been shown essential for cardiac hypertrophy. Our in vitro results with overexpression of miRNA-1 show inhibition of serum-stimulated increase in predicted targets that include RasGAP, Cdk-9, Fibronectin and Rheb, along with protein synthesis and cell size.
MiRNA-21 is increased in various forms of cancer and cardiac hypertrophy. Overexpression of miRNA-21 in myocytes cells show formation of unique type of long extensions, bridging gaps between cells. Target search to explain this phenotype identifies Sprouty2, a known inhibitor of branching morphogenesis. Our results confirm Sprouty2 as a direct target of miRNA-21 under the control of Beta Adrenergic Receptor (É“-AR) stimulation. Independently each of these, overexpression of miRNA-21, É“-AR stimulation and knockdown of sprouty2 results in similar branching pattern, which is inhibited by an anti-21, which we dubbed °•miR-eraser°¶. In myocytes the formed branches are connected thorough functional gap junction potentially for increased conductivity and force transmission.
Based on our results we propose that downregulation of miRNA-1 and upregulation of miRNA-21 seen during hypertrophy have critical autonomous role in the induction and maintenance of cardiac hypertrophy.


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