A Novel Cardiomyocyte-enriched MicroRNA, miR-378, Targets Insulin-like Growth Factor 1 Receptor

Background: Insulin-like growth factor 1 (IGF1)/IGF1R signaling promotes cardiomyocyte survival and undergoes down-regulation after birth. Results: Cardiac expression of miR-378 is induced after birth. IGF1R is a direct target of miR-378. Conclusion: miR-378 promotes cardiac apoptosis. Significance: Inhibition of miR-378 would be beneficial in promoting cardiac cell survival in an ailing heart. Postnatal cardiac remodeling is characterized by a marked decrease in the insulin-like growth factor 1 (IGF1) and IGF1 receptor (IGF1R) expression. The underlying mechanism remains unexplored. This study examined the role of microRNAs in postnatal cardiac remodeling. By expression profiling, we observed a 10-fold increase in miR-378 expression in 1-week-old neonatal mouse hearts compared with 16-day-old fetal hearts. There was also a 4–6-fold induction in expression of miR-378 in older (10 months) compared with younger (1 month) hearts. Interestingly, tissue distribution analysis identified miR-378 to be highly abundant in heart and skeletal muscles. In the heart, specific expression was observed in cardiac myocytes, which was inducible by a variety of stressors. Overexpression of miR-378 enhanced apoptosis of cardiomyocytes by direct targeting of IGF1R and reduced signaling in Akt cascade. The inhibition of miR-378 by its anti-miR protected cardiomyocytes against H2O2 and hypoxia reoxygenation-induced cell death by promoting IGF1R expression and downstream Akt signaling cascade. Additionally, our data show that miR-378 expression is inhibited by IGF1 in cardiomyocytes. In tissues such as fibroblasts and fetal hearts, where IGF1 levels are high, we found either absent or significantly low miR-378 levels, suggesting an inverse relationship between these two factors. Our study identifies miR-378 as a new cardioabundant microRNA that targets IGF1R. We also demonstrate the existence of a negative feedback loop between miR-378, IGF1R, and IGF1 that is associated with postnatal cardiac remodeling and with the regulation of cardiomyocyte survival during stress.

[1]  G. Dorn,et al.  miR-15 Family Regulates Postnatal Mitotic Arrest of Cardiomyocytes , 2011, Circulation research.

[2]  Qiang Yu,et al.  Myc/miR-378/TOB2/cyclin D1 functional module regulates oncogenic transformation , 2011, Oncogene.

[3]  J. Alverdy,et al.  High-molecular-weight polyethylene glycol protects cardiac myocytes from hypoxia- and reoxygenation-induced cell death and preserves ventricular function. , 2011, American journal of physiology. Heart and circulatory physiology.

[4]  E. Olson,et al.  Pervasive roles of microRNAs in cardiovascular biology , 2011, Nature.

[5]  Nicholas Bertos,et al.  miR-378(∗) mediates metabolic shift in breast cancer cells via the PGC-1β/ERRγ transcriptional pathway. , 2010, Cell metabolism.

[6]  M. Periasamy,et al.  Resveratrol, an activator of SIRT1, upregulates sarcoplasmic calcium ATPase and improves cardiac function in diabetic cardiomyopathy. , 2010, American journal of physiology. Heart and circulatory physiology.

[7]  Cam Patterson,et al.  The FoxO family in cardiac function and dysfunction. , 2010, Annual review of physiology.

[8]  D. Catalucci,et al.  Reciprocal Regulation of MicroRNA-1 and Insulin-Like Growth Factor-1 Signal Transduction Cascade in Cardiac and Skeletal Muscle in Physiological and Pathological Conditions , 2009, Circulation.

[9]  Gene Kim,et al.  Sirt3 blocks the cardiac hypertrophic response by augmenting Foxo3a-dependent antioxidant defense mechanisms in mice. , 2009, The Journal of clinical investigation.

[10]  You-yi Zhang,et al.  Upregulated expression of miR-1/miR-206 in a rat model of myocardial infarction. , 2009, Biochemical and biophysical research communications.

[11]  Xiaowei Wang.  A PCR-based platform for microRNA expression profiling studies. , 2009, RNA.

[12]  Y. Pinto,et al.  Conditional Dicer Gene Deletion in the Postnatal Myocardium Provokes Spontaneous Cardiac Remodeling , 2008, Circulation.

[13]  D. Leroith,et al.  Insulin-like growth factor I receptor signaling is required for exercise-induced cardiac hypertrophy. , 2008, Molecular endocrinology.

[14]  Michael D. Schneider,et al.  Targeted deletion of Dicer in the heart leads to dilated cardiomyopathy and heart failure , 2008, Proceedings of the National Academy of Sciences.

[15]  Burton B. Yang,et al.  MicroRNA-378 promotes cell survival, tumor growth, and angiogenesis by targeting SuFu and Fus-1 expression , 2007, Proceedings of the National Academy of Sciences.

[16]  R. Evans,et al.  PGC-1β controls mitochondrial metabolism to modulate circadian activity, adaptive thermogenesis, and hepatic steatosis , 2007, Proceedings of the National Academy of Sciences.

[17]  Richard T. Lee,et al.  Local myocardial insulin-like growth factor 1 (IGF-1) delivery with biotinylated peptide nanofibers improves cell therapy for myocardial infarction. , 2006, Proceedings of the National Academy of Sciences of the United States of America.

[18]  S. Schow,et al.  Diarylureas are small-molecule inhibitors of insulin-like growth factor I receptor signaling and breast cancer cell growth , 2006, Molecular Cancer Therapeutics.

[19]  Eugene Berezikov,et al.  Phylogenetic Shadowing and Computational Identification of Human microRNA Genes , 2005, Cell.

[20]  C. Burge,et al.  Conserved Seed Pairing, Often Flanked by Adenosines, Indicates that Thousands of Human Genes are MicroRNA Targets , 2005, Cell.

[21]  Mark A Sussman,et al.  Cardiac Stem Cell and Myocyte Aging, Heart Failure, and Insulin-Like Growth Factor-1 Overexpression , 2004, Circulation research.

[22]  P. Kang,et al.  The Insulin-like Growth Factor 1 Receptor Induces Physiological Heart Growth via the Phosphoinositide 3-Kinase(p110α) Pathway* , 2004, Journal of Biological Chemistry.

[23]  R. Kitsis,et al.  A mechanistic role for cardiac myocyte apoptosis in heart failure. , 2003, The Journal of clinical investigation.

[24]  A. Samarel.  IGF-1 Overexpression rescues the failing heart. , 2002, Circulation research.

[25]  Mark A Sussman,et al.  Cardiac-Specific IGF-1 Expression Attenuates Dilated Cardiomyopathy in Tropomodulin-Overexpressing Transgenic Mice , 2002, Circulation research.

[26]  I. Tikkanen,et al.  Cardiomyocyte apoptosis and ventricular remodeling after myocardial infarction in rats. , 2001, American journal of physiology. Heart and circulatory physiology.

[27]  Y. Ho,et al.  Overexpression of Bcl-2 attenuates apoptosis and protects against myocardial I/R injury in transgenic mice. , 2001, American journal of physiology. Heart and circulatory physiology.

[28]  R. Kitsis,et al.  The MEK1–ERK1/2 signaling pathway promotes compensated cardiac hypertrophy in transgenic mice , 2000, The EMBO journal.

[29]  R. Kitsis,et al.  Intracoronary, adenovirus-mediated Akt gene transfer in heart limits infarct size following ischemia-reperfusion injury in vivo. , 2000, Journal of molecular and cellular cardiology.

[30]  G. Díaz-Araya,et al.  IGF-1 regulates apoptosis of cardiac myocyte induced by osmotic-stress. , 2000, Biochemical and biophysical research communications.

[31]  J. Sowers,et al.  Insulin-like growth factor I as a cardiac hormone: physiological and pathophysiological implications in heart disease. , 1999, Journal of molecular and cellular cardiology.

[32]  R. Schwartz,et al.  Local insulin‐like growth factor I expression induces physiologic, then pathologic, cardiac hypertrophy in transgenic mice , 1999, FASEB journal : official publication of the Federation of American Societies for Experimental Biology.

[33]  C. di Loreto,et al.  Myocyte death in the failing human heart is gender dependent. , 1999, Circulation research.

[34]  Lei Wang,et al.  Regulation of cardiomyocyte apoptotic signaling by insulin-like growth factor I. , 1998, Circulation research.

[35]  R. Kitsis,et al.  Myocyte apoptosis during acute myocardial infarction in the mouse localizes to hypoxic regions but occurs independently of p53. , 1997, The Journal of clinical investigation.

[36]  C A Beltrami,et al.  Apoptosis in the failing human heart. , 1997, The New England journal of medicine.

[37]  H. Fliss,et al.  Apoptosis in ischemic and reperfused rat myocardium. , 1996, Circulation research.

[38]  P. Anversa,et al.  Acute myocardial infarction in humans is associated with activation of programmed myocyte cell death in the surviving portion of the heart. , 1996, Journal of molecular and cellular cardiology.

[39]  P. Anversa,et al.  Insulin-like growth factor-1 and myocyte growth: the danger of a dogma. Part I. Postnatal myocardial development: normal growth. , 1996, Cardiovascular research.

[40]  E. Sonnenblick,et al.  Fibroblast proliferation during myocardial development in rats is regulated by IGF-1 receptors. , 1995, The American journal of physiology.

[41]  P. Anversa,et al.  Down-regulation of the IGF-1 system parallels the attenuation in the proliferative capacity of rat ventricular myocytes during postnatal development. , 1995, Laboratory investigation; a journal of technical methods and pathology.

[42]  I. Torres-Aleman,et al.  The insulin‐like growth factor I system in the rat cerebellum: Developmental regulation and role in neuronal survival and differentiation , 1994, Journal of neuroscience research.

[43]  E. Kardami.  Stimulation and inhibition of cardiac myocyte proliferation in vitro , 1990, Molecular and Cellular Biochemistry.

[44]  R. Hertzberg,et al.  Camptothecin induces protein-linked DNA breaks via mammalian DNA topoisomerase I. , 1985, The Journal of biological chemistry.