Small molecules - big impact:

New strategy to remedy heart disease through control of micro-RNA-21

Heart cells colored by a flourescent antagomir

30.11.2008, Press releases

Heart disease is among the most common causes of death in our society. An international research team headed by Professor Stefan Engelhardt, newly appointed director of the Institute of Pharmacology and Toxicology at the TU Muenchen (TUM), has now discovered a new approach to preventing or even reversing cardiac damage by regulating the activity of small RNA molecules known as microRNAs. The team’s work has now been published in the online edition of the renowned journal Nature (Nature, Advance Online Publication, November 30, 2008).

Heart disease is the leading cause of death in industrialized countries. And although current therapies can slow down the disease’s progression, they seldom lead to a cure. Researchers in an international team headed by Professor Stefan Engelhardt have made some exciting new discoveries in the treatment of cardiac disease. For this project, Engelhardt’s group collaborated closely with a research team led by Thomas Thum and Johann Bauersachs (Department of Medicine I, at the Würzburg University Clinic, Germany). A significant part of the researchers’ work focuses on the role microRNAs play in the onset of heart disease. The studies – also published in the renowned journal Nature - show a clear link between the concentration of microRNA-21 and damage to cardiac tissue in failing hearts. The concentration of microRNA-21 in such cases is significantly higher than the levels recorded in healthy cardiac tissue. The researchers succeeded in reversing the damage by reducing the concentration of microRNA-21.

The researchers first concentrated on understanding the exact role of microRNA-21 in heart disease. Computer models suggested that microRNA-21 bonds with a messenger RNA known as Spry1, and inhibits its activity. The role of Spry1 is to inhibit outgrowths, where excess fibrous connective tissue cells are formed, resulting in fibrosis as they harden. The scientists found that the computer models were correct – by suppressing Spry1 in another way, they were able to demonstrate the same fibrous effect. Previously, fibrosis was always thought to occur as a result of damage to cardiac muscle cells. Engelhardt’s results now throw a completely new light on this hypothesis. The findings also present a new approach for treating heart failure caused by an excess of microRNA-21.

Antagomirs are complementary synthetic RNA molecules that inhibit microRNA activity, and can therefore be used to silence microRNAs. The teams working under Engelhardt, Thum and Bauersachs proved that cardiac damage resulting from excessive microRNA-21 activity in mice can actually be reduced by administering antagomir-21. Further research carried out at the University of Würzburg revealed that the studies initially performed on mice would also be suitable for human heart trials.

“Existing therapies merely slow down the progression of heart disease; they seldom lead to a cure. For the first time ever, our findings show how this disease could actually be treated through the regulation of microRNA,” explains Stefan Engelhardt. However, several years of intensive research will still be required before this new method becomes available as a drug for humans.

Although microRNAs were discovered 15 years ago, their real impact has only come to light in recent years. A large number of microRNA molecules have now been identified; in fact, there is a microRNA profile for each tissue type. Scientists believe these molecules influence a huge number of different processes. It is also believed that they play a particularly important role in regulating gene expression and protein production.

These studies were financed in part by the Interdisciplinary Center for Research at the University of Würzburg (Interdisziplinäres Zentrum für Klinische Forschung der Universität Würzburg), the German Research Foundation (Deutsche Forschungsgemeinschaft (DFG TH 903/7-1)), the DFG Research Center for Experimental Biomedicine / Rudolf Virchow Center (DFG-Forschungszentrum für Experimentelle Biomedizin / Rudolf Virchow Zentrum), the Bavarian State Ministry of Sciences, Research and the Arts (Bayerische Staatsministerium für Wissenschaft, Forschung und Kunst), ProCorde, Sanofi Aventis SE and the US National Institutes of Health (R01 CA78711).

Original publication: MicroRNA-21 contributes to myocardial disease by stimulating MAP kinase signalling in fibroblasts., Nature, Advance Online Publication, November 30, 2008; Link 

Further information: The French organization Fondation Leducq recently recognized Engelhardt’s achievements by donating about 5 million euros for the creation of a transatlantic network of excellence in cardiac research. This network brings together leading experts from Europe and the USA, enabling them to work together to develop new therapeutic strategies aimed at combating heart disease. The funds will facilitate the exchange of expertise, methods, disease models and reagents between participating research labs and promote, in particular, young scientists. More ...

Contact:

Prof. Dr. Dr. Stefan Engelhardt
Technische Universitaet Muenchen
Institute for Pharmacology and Toxicology
Biedersteiner Straße 29
D 80802 Munich, Germany
Tel.: +49.89.4140.3260
Fax.: +49.89.4140.3261
E-Mail: stefan.engelhardt@tum.de
Web: http://www.ipt.med.tum.de

Prof. Dr. Johann Bauersachs
Universität Würzburg,
Josef-Schneider-Str. 2
D 97080 Wuerzburg, Germany
Tel.: +49.931.201.36134
E-Mail: Bauersachs_J@klinik.uni-wuerzburg.de

Dr. Dr. Thomas Thum
Universität Würzburg,
Josef-Schneider-Str. 2
D 97080 Wuerzburg, Germany
Tel.: +49.931.201.36455
Tel.: +49.931.201.36664
E-Mail: Thum_T@klinik.uni-wuerzburg.de

Kontakt: presse@tum.de

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