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MiR-378 Controls Cardiac Hypertrophy by Combined Repression of MAP Kinase Pathway Factors

Transfection of miR-378 inhibits phenylephrine (PE)-induced hypertrophy of primary cardiomyocytes.

(April 2013) MicroRNAs (miRs) are small, noncoding RNAs that posttranscriptionally regulate gene expression. Thus, miRs have been shown to regulate many processes in health and disease, including cardiovascular disease. Using a method to screen libraries of multiple synthetic miRs for the induction of cardiomyocyte hypertrophy, a hallmark of the myocardial stress response, a research team led by Stefan Engelhardt at the Institute of Pharmacology at TUM had found the first evidence for an antihypertrophic activity of miR-378 in the myocardium. Subsequent analyses carried out by Jaya Ganesan, a PhD student at the Institute of Pharmacology and Toxicology now showed that miR-378 represses prohypertrophic signaling at four levels within the mitogen-activated protein kinase signaling pathway. MiR-378 was found to be downregulated both in animal models of myocardial disease and in human failing myocardium. Compensation for miR-378 downregulation in a cardiac disease model using viral gene transfer in vivo protected the heart against hypertrophy and dysfunction. Together, these data indicate effective interference of miR-378 with a key prohypertrophic signaling pathway. Targeted delivery of miR-378 to the heart may prove to be an effective therapeutic strategy in myocardial disease. For further reading see undefinedCirculation, published online April 26th, 2013.

Heart Researcher Wins Developmental Bio Prize

(March 2013) Insights into the mysteries of the heart have earned Eric Olson the 2013 March of Dimes Prize in Developmental Biology. He will receive the $250,000 prize in Washington, D.C.

Olson studies the genetic signals that control heart development at the University of Texas Southwestern Medical Center in Dallas. He and his colleagues have shown that newborn mouse hearts can regenerate to a suprising degree in the first week after birth (Science, 25 February 2011, p. 1078). They have also found a suite of proteins and microRNAs that promote regeneration in older mouse hearts.

4th Meeting of the Transatlantic Network of Excellence on MicroRNAs (Leducq)

Keynote lecture by Prof. Irene Bozzoni from the University of Rome on Noncording RNAs

(September 2012) On September 19th - 21st Leon de Windt and team organized the 4th annual meeting of the microRNA research consortium. The two day scientific program contained seminars hold by all principal investigators as well as by junior team members. Additional lectures were given by the associate investigators Eva vanRooij and Annick Harel-Bellan. A keynote lecture on noncoding RNAs was given by Irene Bozzoni from the University of Rome.

ERC consolidator grant for Leon de Windt

BRUSSELS, BELGIUM (01-09-2012) - Prof. Leon de Windt is the recipient of a prestigious grant of the European Research Council (ERC). ERC Consolidator Grants are designed to support researchers at the stage at which they are consolidating their own independent research team or program. The scheme will strengthen independent and excellent new individual research teams that have been recently created. Applicants for the ERC Consolidator Grants - called Principal Investigators (PI) - must have already shown the potential for research independence and evidence of scientific maturity. Applicants should also be able to demonstrate a promising track-record of early achievements appropriate to their research field and career stage, including significant publications (as main author) in major international peer-reviewed multidisciplinary scientific journals, or in the leading international peer-reviewed journals of their respective field.

Pervasive roles of microRNAs in cardiovascular biology.

(January 2011) First recognized as regulators of development in worms and fruitflies, microRNAs are emerging as pivotal modulators of mammalian cardiovascular development and disease. Individual microRNAs modulate the expression of collections of messenger RNA targets that often have related functions, thereby governing complex biological processes. The wideranging functions of microRNAs in the cardiovascular system have provided new perspectives on disease mechanisms and have revealed intriguing therapeutic targets, as well as diagnostics, for a variety of cardiovascular disorders.

Concepts of miRNA function. The potential modes of miRNA-based regulation of gene expression are shown. a, Intronic miRNAs are encoded within an intron of a host gene. mRNA splicing generates a protein-coding transcript and an miRNA stem–loop. Intronic miRNAs often regulate similar processes to that of the protein encoded by the host gene. AAA, polyadenylated tail of the transcript; pre-miRNA, precursor miRNA. b, A common mechanism of miRNA function involves the modest repression of several mRNAs in a common biological process by a single miRNA. This mechanism reduces the dependence on a single miRNA-mRNA interaction and increases the robustness of the gene-regulatory network. TF, transcription factor. c, Many miRNAs may cooperatively or redundantly regulate a single biological process, by individually targeting many components of that process or by synergistically repressing a crucial component of a pathway. d, miRNAs may act as a ‘buffer’ against minor perturbations in a biological pathway. This is accomplished by the targeting of factors that positively and negatively influence a particular process, thereby insulating that process from environmental fluctuations.

Small EM, Olson EN. Pervasive roles of microRNAs in cardiovascular biology. Nature 2011 Jan 20;469(7330):336-42.

Career Development Award for Paula da Costa Martins

Dr. da Costa Martins is a junior group leader at the Cardiovascular Research Institute Maastricht, where her work is embedded in the research group of Dr. Leon de Windt, member of the MicroRNAs as therapeutic targets in heart failure network.

Dr. da Costa Martins currently focuses on microRNA biology and recently was the lead author of a publication in Nature Cell Biology about microRNA-199b in heart failure. MicroRNA 216a (miR-216a) also appears to be important in this condition. MiR-216a is thought to act upon genes involved in autophagy, a tightly controlled process by which a cell's components are degraded and recycled. It is likely that when blood supply is restricted, either insufficient or excessive autophagy leads to cell death and subsequent heart failure.

With her award, Dr. da Costa Martins will split her time between Maastricht and Dallas, where she will work with Dr. Eric Olson, the North American coordinator of the network, at the University of Texas, Southwestern. Her key objectives are to identify the genes regulated by miR-216a, to determine whether miR-216a is necessary for cell death, and to establish whether silencing miR-216a has therapeutic benefit.

MicroRNA-218 regulates vascular patterning by modulation of Slit-Robo signaling.

miR-218 contributes to angiogenesis. Vasculature of the retina at P7, as visualized by isolectin staining in flat mount preparation. Top row (a through c) is representative control oligonucleotide injected retina, and bottom row (d through f) is LNA anti–miR-218–injected. High magnification confocal images of migration front of control injected (c) and LNA miR-218–injected (f) retinas reveals altered EC plexus morphology. Arrows mark tip cells and arrowheads mark EC projections failing to make interconnections. Scale bars: 500 µm (a and d); 200 µm (b and e); and 20 µm (c and f).

(November 2010) Establishment of a functional vasculature requires the interconnection and remodeling of nascent blood vessels. Precise regulation of factors that influence endothelial cell migration and function is essential for these stereotypical vascular patterning events. The secreted Slit ligands and their Robo receptors constitute a critical signaling pathway controlling the directed migration of both neurons and vascular endothelial cells during embryonic development, but the mechanisms of their regulation are incompletely understood.  Eric Olson and colleagues provide evidence that microRNA (miR)-218, which is encoded by an intron of the Slit genes, inhibits the expression of Robo1 and Robo2 and multiple components of the heparan sulfate biosynthetic pathway. Using in vitro and in vivo approaches, we demonstrate that miR-218 directly represses the expression of Robo1, Robo2, and glucuronyl C5-epimerase (GLCE), and that an intact miR-218-Slit-Robo regulatory network is essential for normal vascularization of the retina. Knockdown of miR-218 results in aberrant regulation of this signaling axis, abnormal endothelial cell migration, and reduced complexity of the retinal vasculature. Our findings link Slit gene expression to the posttranscriptional regulation of Robo receptors and heparan sulfate biosynthetic enzymes, allowing for precise control over vascular guidance cues influencing the organization of blood vessels during development.

Small EM, Sutherland LB, Rajagopalan KN, Wang S, Olson EN. MicroRNA-218 regulates vascular patterning by modulation of Slit-Robo signaling. Circ Res 2010 Nov 26;107(11):1336-44. Epub 2010 Oct 14.

Defective erythroid differentiation in miR-451 mutant mice mediated by 14-3-3zeta.

miR-451 is expressed in erythrocytes, and miR-451−/− mice display a reduction in hematocrit. Expression of β-gal driven by the miR-451 enhancer is restricted to the circulatory system at 13.5 dpc. Cross-section through the intersomitic veins reveals β-gal positivity of circulating erythrocytes.

(August 2010) Erythrocyte formation occurs throughout life in response to cytokine signaling. Eric Olson and colleagues showed that microRNA-451 (miR-451) regulates erythropoiesis in vivo. Mice lacking miR-451 displayed a reduction in hematrocrit, an erythroid differentiation defect, and ineffective erythropoiesis in response to oxidative stress. 14-3-3zeta, an intracellular regulator of cytokine signaling that is repressed by miR-451, was up-regulated in miR-451(-/-) erythroblasts, and inhibition of 14-3-3zeta rescues their differentiation defect. These findings revealed an essential role of 14-3-3zeta as a mediator of the proerythroid differentiation actions of miR-451, and highlight the therapeutic potential of miR-451 inhibitors.

Patrick DM, Zhang CC, Tao Y, Yao H, Qi X, Schwartz RJ, Jun-Shen Huang L, Olson EN. Defective erythroid differentiation in miR-451 mutant mice mediated by 14-3-3zeta. Genes Dev 2010 Aug 1;24(15):1614-9.






Regulation of PI3-kinase/Akt signaling by muscle-enriched microRNA-486.

Proposed model of miR-486 regulation and function in muscle cells. miR-486 transcription is activated by MyoD and MRTF-A. miR-486 directly represses the translation of PTEN and Foxo1a, two crucial negative regulators of PI3K/Akt signaling, resulting in the phosphorylation of Akt and the activation of the pathway. Activated Akt results in the phosphorylation of GSK3β and the inhibition of Foxo1a activity.

(March 2010) MicroRNAs (miRNAs) play key roles in modulating a variety of cellular processes through repression of mRNA targets. In a screen for miRNAs regulated by myocardin-related transcription factor-A (MRTF-A), a coactivator of serum response factor (SRF), Eric Olson and colleagues discovered a muscle-enriched miRNA, miR-486, controlled by an alternative promoter within intron 40 of the Ankyrin-1 gene. Transcription of miR-486 is directly controlled by SRF and MRTF-A, as well as by MyoD. Among the most strongly predicted targets of miR-486 are phosphatase and tensin homolog (PTEN) and Foxo1a, which negatively affect phosphoinositide-3-kinase (PI3K)/Akt signaling. Accordingly, PTEN and Foxo1a protein levels are reduced by miR-486 overexpression, which, in turn, enhances PI3K/Akt signaling. Similarly, we show that MRTF-A promotes PI3K/Akt signaling by up-regulating miR-486 expression. Conversely, inhibition of miR-486 expression enhances the expression of PTEN and Foxo1a and dampens signaling through the PI3K/Akt-signaling pathway. Our findings implicate miR-486 as a downstream mediator of the actions of SRF/MRTF-A and MyoD in muscle cells and as a potential modulator of PI3K/Akt signaling. 

Small EM, O'Rourke JR, Moresi V, Sutherland LB, McAnally J, Gerard RD, Richardson JA, Olson EN. Regulation of PI3-kinase/Akt signaling by muscle-enriched microRNA-486. Proc Natl Acad Sci U S A. 2010 Mar 2;107(9):4218-23.

Network Meeting in Italy

(October 2009) The first annual “MicroRNAs As Therapeutic Targets In Heart Failure” Leducq meeting was hosted by Gianluigi Condorelli on October 2-3, 2009 in Capri, Italy.  The Core members, Eric Olson, Stefan Engelhardt, Markus Stoffel, Leon deWindt and Gianluigi Condorelli were in attendance with postdoctoral fellows and students from their labs.  Also, in attendance were Associate members, Eva van Rooij and Annick Harel-Bellan. Students and postdoctoral fellows from each lab presented their data pertaining to the grant proposal and lively discussions followed the presentations. Significant time on the second day of the meeting was denoted to measures how to further optimize this transatlantic network.

The core members agreed on the following actions:

  1. Increase collaboration among labs (encourage postdoc/student exchange)
  2. Share recombinant viruses (provide list of viruses from each lab)
  3. Share plasmids (cDNAs and luciferase reporters) and  provide lists of plasmids and other reagents available from each lab
  4. Provide list of transgenic and KO mice generated in each lab
  5. Provide list of antagomirs, anti-miRs and mimics available in each lab
  6. Share protocols among labs

Suggestions for next year’s meeting include: Inviting a guest speaker (another Leducq member) and providing a workshop on a specific topic.



DeWindt laboratory moves to Maastricht University

(September 2009) The research group headed by Leon de Windt, core member of the microRNA Leducq consortium, has moved to Maastricht University to become embedded within the School for Cardiovascular Diseases, the largest of its kind in the Netherlands. Leon de Windt was appointed as Full Professor at the Department of Cardiology to run a research program in Molecular Cardiovascular Biology, of which his research in the microRNA Leducq network forms a vital part.

Maastricht University and the University Medical Center are located at the campus of the Faculty of Health, Medicine and Life Sciences. Maastricht University is consistently ranked among the top in the Netherlands and Europe for its quality of teaching.

Located on the most southern tip of the Netherlands, situated on both sides of the river Meuse, Maastricht is widely known as a centre of tradition, history and culture, and popular with tourists for shopping and recreation. The city borders to Belgium and Germany, knows a dense concentration of educational establishments and has a large international student population. The city's name is derived from Latin Trajectum ad Mosam or Mosae Trajectum, meaning "Mosa-crossing", and refers to the bridge over the Meuse river built by the Romans during the reign of Augustus Caesar. As such, Maastricht is considered the oldest city in the Netherlands and retained many of its historical buildings.

Stefan Engelhardt receives Outstanding Achievement Award from the ESC

(August 2009) Stefan Engelhardt received this year´s Outstanding Achievement Award from the European Society of Cardiology (ESC). The award will be presented by the Council of Basic Cardiovascular Research at the Annual ESC-congress in Barcelona, Spain.






Eric Olson wins Institut de France’s prestigious Lefoulon-Delalande Foundation Grand Prize

Dr. Eric Olson, American coordinator of the Leducq Network on MicroRNAs as therapeutic targets in heart failure

(June 2009) Eric Olson, chairman of molecular biology at
UT Southwestern Medical Center, has been awarded the Institut de France’s prestigious Lefoulon-Delalande Foundation Grand Prize for his work on gene regulation in the cardiovascular system.

The prize has an international reputation as the most prestigious award in cardiovascular research. The award of about $664,000 (500,000 euros) will be presented June 10 in France by French Prime Minister Francois Fillon and the president of the Institut de France.

“I consider this award one of the highest honors of my career,” Dr. Olson said. “It’s a wonderful recognition of the many scientists in my lab from throughout the United States and around the world who have contributed to this effort.  They really deserve the credit.”

microRNA-133a regulates cardiomyocyte proliferation and suppresses smooth muscle gene expression in the heart

(December 2008) miR-133a-1 and miR-133a-2 are identical, muscle-specific miRNAs that are regulated during muscle development by the SRF transcription factor. We show that mice lacking either miR-133a-1 or miR-133a-2 are normal, whereas deletion of both miRNAs causes lethal ventricular-septal defects in approximately half of double-mutant embryos or neonates; miR-133a double-mutant mice that survive to adulthood succumb to dilated cardiomyopathy and heart failure.

The absence of miR-133a expression results in ectopic expression of smooth muscle genes in the heart and aberrant cardiomyocyte proliferation. These abnormalities can be attributed, at least in part, to elevated expression of SRF and cyclin D2, which are targets for repression by miR-133a. These findings reveal essential and redundant roles for miR-133a-1 and miR-133a-2 in orchestrating cardiac development, gene expression, and function and point to these miRNAs as critical components of an SRF-dependent myogenic transcriptional circuit.

Liu N, Bezprozvannaya S, Williams AH, Qi X, Richardson JA, Bassel-Duby R, Olson EN. microRNA-133a regulates cardiomyocyte proliferation and suppresses smooth muscle gene expression in the heart. Genes Dev. 2008 Dec 1;22(23):3242-54.

MicroRNA-21 contributes to myocardial disease by stimulating MAPkinase signalling in fibroblasts

Uptake of a fluorescently labelled microRNA-antagonist into cardiac tissue

(December 2008) MicroRNAs comprise a broad class of small non-coding RNAs that control expression of complementary target messenger RNAs. Carina Gross and Thomas Fischer from the laboratory of Stefan Engelhardt in close collaboration with Thomas Thum and Johann Bauersachs (Medizinische Klinik I, Universität Würzburg) have developed a novel therapeutic approach to treat cardiac failure. They found strongly enhanced levels of a small microRNA, microRNA-21, in the myocardium of failing hearts. This microRNA inhibits the formation of the endogenous MAPkinase inhibitor Sprouty-1, effectively augmenting Erk-MAPkinase-activity in cardiac fibroblasts. This mechanism regulates fibroblast survival and growth factor secretion, apparently controlling the extent of interstitial fibrosis and cardiac hypertrophy. In vivo silencing of miR-21 by a specific antagomir in a mouse pressure-overload-induced disease model reduced cardiac ERK–MAP kinase activity, inhibited interstitial fibrosis and attenuated cardiac dysfunction. These findings reveal that microRNAs can contribute to myocardial disease by an effect in cardiac fibroblasts. Our results validate miR-21 as a disease target in heart failure and establish the therapeutic efficacy of microRNA therapeutic intervention in a cardiovascular disease setting.

Thum T, Gross C, Fiedler J, Fischer T, Kissler S, Bussen M, Galuppo P, Just S, Rottbauer W, Frantz S, Castoldi M, Soutschek J, Koteliansky V, Rosenwald A, Basson MA, Licht JD, Pena JT, Rouhanifard SH, Muckenthaler MU, Tuschl T, Martin GR, Bauersachs J & Engelhardt S. MicroRNA-21 contributes to myocardial disease by stimulating MAP kinase signalling in fibroblasts. Nature 2008 Nov 30. [Epub ahead of print]

Eric Olson receives AHA National Research Achievement Award

 (November 2008) Eric N. Olson received the American Heart Association National Research Achievement Award. He was honored for making major discoveries identifying molecular mechanisms that control normal and abnormal growth and development of the heart and cardiovascular system.

Conditional dicer gene deletion in the postnatal myocardium provokes spontaneous cardiac remodeling

Dicer-deficient mice develop cardiac failure

(October 2008) Dicer, an RNAse III endonuclease critical for processing of pre-microRNAs (miRNAs) into mature 22-nucleotide miRNAs, has proven a useful target to dissect the significance of miRNAs biogenesis in mammalian biology. To circumvent the embryonic lethality associated with germline null mutations for Dicer, we triggered conditional Dicer loss through the use of a tamoxifen-inducible Cre recombinase in the postnatal murine myocardium. Targeted Dicer deletion in 3-week-old mice provoked premature death within 1 week accompanied by mild ventricular remodeling and dramatic atrial enlargement. In the adult myocardium, loss of Dicer induced rapid and dramatic biventricular enlargement, accompanied by myocyte hypertrophy, myofiber disarray, ventricular fibrosis, and strong induction of fetal gene transcripts. Comparative miRNA profiling revealed a set of miRNAs that imply causality between miRNA depletion and spontaneous cardiac remodeling. Overall, these results indicate that modifications in miRNA biogenesis affect both juvenile and adult myocardial morphology and function.

da Costa Martins PA, Bourajjaj M, Gladka M, Kortland M, van Oort RJ, Pinto YM, Molkentin JD & De Windt LJ. Conditional dicer gene deletion in the postnatal myocardium provokes spontaneous cardiac remodeling. Circulation. 2008 Oct 7;118(15):1567-76.