MicroRNA-30b-5p Is Involved in the Regulation of Cardiac Hypertrophy by Targeting CaMKIIδ

Background MicroRNAs (miRNAs) participate in the regulation of cardiac hypertrophy. However, it remains largely unknown as to how miRNAs are integrated into the hypertrophic program. Ca2+/calmodulin-dependent protein kinase II (CaMKII) is a hypertrophic signaling marker. It is not yet clear which miRNAs can regulate CaMKIIδ. Purpose In this study, we identified which miRNAs could regulate CaMKIIδ and how to regulate CaMKIIδ. Methods Through computational and expression analyses, miR-30b-5p was identified as a candidate regulator of CaMKIIδ. Quantitative expression analysis of hypertrophic models demonstrated significant down-regulation of miR-30b-5p compared with control groups. Luciferase reporter assay showed that miR-30b-5p could significantly inhibit the expression of CaMKIIδ. Moreover, through gain-of-function and loss-of-function approaches, we found miR-30b-5p could negatively regulate the expression of CaMKIIδ and miR-30b-5p was a regulator of cardiac hypertrophy. Conclusion Our study demonstrates that the expression of miR-30b-5p is down-regulated in cardiac hypertrophy, and restoration of its function inhibits the expression of CaMKIIδ, suggesting that miR-30b-5p may act as a hypertrophic suppressor.

[1]  V. Ambros,et al.  The C. elegans heterochronic gene lin-4 encodes small RNAs with antisense complementarity to lin-14 , 1993, Cell.

[2]  H. Schulman,et al.  The multifunctional calcium/calmodulin-dependent protein kinase: from form to function. , 1995, Annual review of physiology.

[3]  Jeffrey Robbins,et al.  A Calcineurin-Dependent Transcriptional Pathway for Cardiac Hypertrophy , 1998, Cell.

[4]  R Hetzer,et al.  Identification and expression of delta-isoforms of the multifunctional Ca2+/calmodulin-dependent protein kinase in failing and nonfailing human myocardium. , 1999, Circulation research.

[5]  A. Means,et al.  Regulatory cascades involving calmodulin-dependent protein kinases. , 2000, Molecular endocrinology.

[6]  E. Olson,et al.  Activated MEK5 induces serial assembly of sarcomeres and eccentric cardiac hypertrophy , 2001, The EMBO journal.

[7]  Tong Zhang,et al.  The Cardiac-specific Nuclear δB Isoform of Ca2+/Calmodulin-dependent Protein Kinase II Induces Hypertrophy and Dilated Cardiomyopathy Associated with Increased Protein Phosphatase 2A Activity* , 2002, The Journal of Biological Chemistry.

[8]  A. Ferrari,et al.  Attenuation of aortic banding-induced cardiac hypertrophy by propranolol is independent of β-adrenoceptor blockade , 2002, Journal of hypertension.

[9]  T. Tuschl,et al.  New microRNAs from mouse and human. , 2003, RNA.

[10]  I. Shiojima,et al.  Akt Activity Negatively Regulates Phosphorylation of AMP-activated Protein Kinase in the Heart* , 2003, Journal of Biological Chemistry.

[11]  J. M. Turbeville,et al.  Organization and evolution of multifunctional Ca(2+)/CaM-dependent protein kinase genes. , 2003, Gene.

[12]  A. Means,et al.  Pressure overload selectively up-regulates Ca2+/calmodulin-dependent protein kinase II in vivo. , 2003, Molecular endocrinology.

[13]  Tong Zhang,et al.  The &dgr;C Isoform of CaMKII Is Activated in Cardiac Hypertrophy and Induces Dilated Cardiomyopathy and Heart Failure , 2003, Circulation research.

[14]  E. Olson,et al.  Cardiac hypertrophy: the good, the bad, and the ugly. , 2003, Annual review of physiology.

[15]  C. Burge,et al.  Prediction of Mammalian MicroRNA Targets , 2003, Cell.

[16]  S. Miyamoto,et al.  Cardiomyocyte calcium and calcium/calmodulin-dependent protein kinase II: friends or foes? , 2004, Recent progress in hormone research.

[17]  Rick B. Vega,et al.  Protein Kinases C and D Mediate Agonist-Dependent Cardiac Hypertrophy through Nuclear Export of Histone Deacetylase 5 , 2004, Molecular and Cellular Biology.

[18]  L. Maier CaMKIIdelta overexpression in hypertrophy and heart failure: cellular consequences for excitation-contraction coupling. , 2005, Brazilian journal of medical and biological research = Revista brasileira de pesquisas medicas e biologicas.

[19]  Anton J. Enright,et al.  Materials and Methods Figs. S1 to S4 Tables S1 to S5 References and Notes Micrornas Regulate Brain Morphogenesis in Zebrafish , 2022 .

[20]  Guy Salama,et al.  Calmodulin kinase II inhibition protects against structural heart disease , 2005, Nature Medicine.

[21]  J. Molkentin,et al.  Regulation of cardiac hypertrophy by intracellular signalling pathways , 2006, Nature Reviews Molecular Cell Biology.

[22]  Kaleb M. Pauley,et al.  Formation of GW bodies is a consequence of microRNA genesis , 2006, EMBO reports.

[23]  Noam Shomron,et al.  Canalization of development by microRNAs , 2006, Nature Genetics.

[24]  E. Olson,et al.  A signature pattern of stress-responsive microRNAs that can evoke cardiac hypertrophy and heart failure , 2006, Proceedings of the National Academy of Sciences.

[25]  N. Rajewsky microRNA target predictions in animals , 2006, Nature Genetics.

[26]  Xiaoxia Qi,et al.  Control of Stress-Dependent Cardiac Growth and Gene Expression by a MicroRNA , 2007, Science.

[27]  C. Croce,et al.  MicroRNA-133 controls cardiac hypertrophy , 2007, Nature Medicine.

[28]  J. G. Patton,et al.  Zebrafish miR-214 modulates Hedgehog signaling to specify muscle cell fate , 2007, Nature Genetics.

[29]  Danish Sayed,et al.  MicroRNAs Play an Essential Role in the Development of Cardiac Hypertrophy , 2007, Circulation research.

[30]  D. Black,et al.  MicroRNAs regulate the expression of the alternative splicing factor nPTB during muscle development. , 2007, Genes & development.

[31]  T. McKinsey Derepression of pathological cardiac genes by members of the CaM kinase superfamily. , 2007, Cardiovascular research.

[32]  L. Ruilope,et al.  Left ventricular hypertrophy and clinical outcomes in hypertensive patients. , 2008, American journal of hypertension.

[33]  Mi-Sung Kim,et al.  Requirement of protein kinase D1 for pathological cardiac remodeling , 2008, Proceedings of the National Academy of Sciences.

[34]  N. Rajewsky,et al.  Widespread changes in protein synthesis induced by microRNAs , 2008, Nature.

[35]  D. Bartel,et al.  The impact of microRNAs on protein output , 2008, Nature.

[36]  Tong Zhang,et al.  Requirement for Ca2+/calmodulin-dependent kinase II in the transition from pressure overload-induced cardiac hypertrophy to heart failure in mice. , 2009, The Journal of clinical investigation.

[37]  D. Bartel MicroRNAs: Target Recognition and Regulatory Functions , 2009, Cell.

[38]  Chunxiang Zhang,et al.  MicroRNA Expression Signature and the Role of MicroRNA-21 in the Early Phase of Acute Myocardial Infarction* , 2009, The Journal of Biological Chemistry.

[39]  Hugo A. Katus,et al.  The δ isoform of CaM kinase II is required for pathological cardiac hypertrophy and remodeling after pressure overload , 2009, Proceedings of the National Academy of Sciences.

[40]  T. Golub,et al.  MicroRNA-1 Negatively Regulates Expression of the Hypertrophy-Associated Calmodulin and Mef2a Genes , 2009, Molecular and Cellular Biology.

[41]  R. Duisters,et al.  MIRNA-133 AND MIRNA-30 REGULATE CONNECTIVE TISSUE GROWTH FACTOR: IMPLICATIONS FOR A ROLE OF MIRNAS IN MYOCARDIAL MATRIX REMODELING , 2013 .

[42]  Marc Rehmsmeier,et al.  Comprehensive prediction of novel microRNA targets in Arabidopsis thaliana , 2009, Nucleic acids research.

[43]  P. Tam Faculty Opinions recommendation of miR-145 and miR-143 regulate smooth muscle cell fate and plasticity. , 2009 .

[44]  F. Yu,et al.  Mir-30 reduction maintains self-renewal and inhibits apoptosis in breast tumor-initiating cells , 2010, Oncogene.

[45]  Jincheng Li,et al.  miR-30 Regulates Mitochondrial Fission through Targeting p53 and the Dynamin-Related Protein-1 Pathway , 2010, PLoS genetics.

[46]  S. Reiken,et al.  Role of CaMKIIδ phosphorylation of the cardiac ryanodine receptor in the force frequency relationship and heart failure , 2010, Proceedings of the National Academy of Sciences.

[47]  J. Steitz,et al.  miR-29 and miR-30 regulate B-Myb expression during cellular senescence , 2010, Proceedings of the National Academy of Sciences.

[48]  Jing Wang,et al.  Ca2+/calmodulin‐dependent protein kinase IIδ orchestrates G‐protein‐coupled receptor and electric field stimulation‐induced cardiomyocyte hypertrophy , 2010, Clinical and experimental pharmacology & physiology.

[49]  H. Dralle,et al.  Downregulation of microRNAs directs the EMT and invasive potential of anaplastic thyroid carcinomas , 2010, Oncogene.

[50]  C. Dani,et al.  Small RNA sequencing reveals miR-642a-3p as a novel adipocyte-specific microRNA and miR-30 as a key regulator of human adipogenesis , 2011, Genome Biology.

[51]  Feng-lan Li,et al.  Aberrant expression profiles of isoproterenol‐induced endoplasmic reticulum stress response genes in mouse myocardium , 2011, Journal of biochemical and molecular toxicology.

[52]  Peilong Li,et al.  MicroRNAs in cardiac hypertrophy: angels or devils , 2011, Wiley interdisciplinary reviews. RNA.

[53]  F. Jaffrézic,et al.  Overexpression of miR-30b in the Developing Mouse Mammary Gland Causes a Lactation Defect and Delays Involution , 2012, PloS one.

[54]  Junfeng Zhang,et al.  miR-30 inhibits TGF-β1-induced epithelial-to-mesenchymal transition in hepatocyte by targeting Snail1. , 2012, Biochemical and biophysical research communications.

[55]  Donald M. Bers,et al.  Requirement for Ca 2+/calmodulin-dependent kinase II in the transition from pressure overload-induced cardiac hypertrophy to heart failure in mice (Journal of Clinical Investigation (2009) 119, 5, (1230-1240) doi: 10.1172/JCI38022) , 2012 .

[56]  Haibo Zhou,et al.  miR-30 Family Members Negatively Regulate Osteoblast Differentiation* , 2012, The Journal of Biological Chemistry.