The gene, Ephx2, encodes an enzyme (soluble epoxide hydrolase) that normally degrades specific epoxides. In this case, the epoxides can be cardioprotective in the setting of heart failure but not necessarily relevant for healthy individuals. In persons with heart failure, a low Ephx2 activity would not break down the epoxides and as a result, the heart could be protected from further damage.
However, in persons with both heart failure and an altered Ephx2 gene resulting in a hyperactive soluble epoxide hydrolase, the epoxides would be degraded. This state-of-affairs would worsen the heart failure condition. The Ephx2 gene was identified by the physicians Dr. Jan Monti, Prof. Friedrich Luft (both Charité-Universitätsmedizin Berlin/Helios Klinikum Berlin-Buch), and the genome researcher Prof. Norbert Hübner (Max Delbrück Center for Molecular Medicine, MDC, Berlin-Buch), as well as by their collaborators. The results were published online in the current issue of the journal Nature Genetics (Vol. 40, No. 5, pp. 529 - 537, 2008)*. The scientists hope that their results might improve the diagnosis and therapy for heart failure.
According to the American Heart Association, more than 57,000 Americans died of heart failure in 2004. The number of Europeans is larger still. Heart failure is the third most common cause of death in Western countries, after coronary heart disease and stroke. Heart failure commonly results from coronary disease and hypertension.
Heart failure usually develops over a longer period of time and is therefore commonly seen in older individuals. When the heart is no longer able to pump enough blood to meet the body's requirements, the heart muscle enlarges in an effort to compensate. However, often the heart does not overcome the increased burden and becomes weakened further, especially in cases of pre-existing hypertension. "But elevated blood pressure does not necessarily cause heart failure in all patients," Dr. Monti, physician at the Charité and Helios, explains. "Hypertension damages the heart and increases the propensity to develop heart failure. Other factors also contribute to the disease."
The spontaneously hypertensive stroke-prone (SHRSP) rat strain, which is characterized by severe hypertension, does not develop heart failure. In contrast, the spontaneously hypertensive heart failure (SHHF) rat strain regularly develops heart failure as a result of hypertension. The investigators capitalized on these observations to answer the question, "why?" When comparing both strains, the researchers observed that SHHF rats possess genetic variations that are not present in SHRSP rats. These single base pair variations are called "single nucleotide polymorphisms" (SNPs). "In SHHF rats, SNPs in the gene called Ephx2 lead to an increased production of the enzyme soluble epoxide hydrolase," Prof. Hübner explains. He is the genome researcher from the MDC who conceived the project.The body's "self aid" drops out
The soluble epoxide hydrolase was long suspected to play a role in the development of heart failure. "But a candidate gene is not a proof", notes Prof. Luft. "It took more than four years for numerous researchers working together to gather convincing evidence about the candidate gene." Clinicians and scientists now hope for the development of new diagnostic and therapeutic options. "Animal experiments with inhibitors of the soluble epoxide hydrolase are in progress," Dr. Monti comments. "However, a gene deletion in a mouse is not necessarily the same as an inhibitory drug. The way into the clinical arena is long and arduous."*Soluble epoxide hydrolase is a susceptibility gene for heart failure in a rat model of human disease
Jan Monti1,2,9, Judith Fischer1,9, Svetlana Paskas1, Matthias Heinig1,3, Herbert Schulz1, Claudia Gösele1, Arnd Heuser1,2, Robert Fischer1,2, Cosima Schmidt1, Alexander Schirdewan2, Volkmar Gross1, Oliver Hummel1, Henrike Maatz1, Giannino Patone1, Kathrin Saar1, Martin Vingron3, Steven M Weldon4, Klaus Lindpaintner5, Bruce D Hammock6, Klaus Rohde1, Rainer Dietz1,2, Stuart A Cook7, Wolf-Hagen Schunck1, Friedrich C Luft1,8 & Norbert Hubner1
1Max-Delbrück Center for Molecular Medicine, Robert-Rössle-Strasse 10, 13125 Berlin, Germany. 2Department of Clinical and Molecular Cardiology, Franz-Volhard Clinic, HELIOS, Charite´ -Universitätsmedizin Berlin, Schwanebecker Chaussee 50, 13125 Berlin, Germany. 3Department of Bioinformatics, Max-Planck-Institute for Molecular Genetics, Ihnestraße 63-73, 14195 Berlin, Germany. 4Boehringer Ingelheim Pharmaceuticals Inc., 900 Ridgebury Road, Ridgefield, Connecticut 06877-0368, USA. 5F. Hoffmann-La Roche, Grenzacherstrasse 124, 4070 Basel, Switzerland. 6Departments of Entomology and Nutrition and Cancer Research Center, University of California at Davis, One Shields Avenue, Davis, California 95616-8584, USA. 7MRC Clinical Sciences Centre, Faculty of Medicine, Imperial College London, South Kensington Campus, London SW7 2AZ, UK. 8Department of Nephrology/Hypertension, Franz-Volhard Clinic, HELIOS, Charité -Universitätsmedizin Berlin, Schwanebecker Chaussee 50, 13125 Berlin, Germany. 9These authors contributed equally to this work.Barbara Bachtler
Barbara Bachtler | Max-Delbrück-Centrum
Clock stars: Astrocytes keep time for brain, behavior
27.03.2017 | Washington University in St. Louis
Cryo-electron microscopy achieves unprecedented resolution using new computational methods
24.03.2017 | DOE/Lawrence Berkeley National Laboratory
Astronomers from Bonn and Tautenburg in Thuringia (Germany) used the 100-m radio telescope at Effelsberg to observe several galaxy clusters. At the edges of these large accumulations of dark matter, stellar systems (galaxies), hot gas, and charged particles, they found magnetic fields that are exceptionally ordered over distances of many million light years. This makes them the most extended magnetic fields in the universe known so far.
The results will be published on March 22 in the journal „Astronomy & Astrophysics“.
Galaxy clusters are the largest gravitationally bound structures in the universe. With a typical extent of about 10 million light years, i.e. 100 times the...
Researchers at the Goethe University Frankfurt, together with partners from the University of Tübingen in Germany and Queen Mary University as well as Francis Crick Institute from London (UK) have developed a novel technology to decipher the secret ubiquitin code.
Ubiquitin is a small protein that can be linked to other cellular proteins, thereby controlling and modulating their functions. The attachment occurs in many...
In the eternal search for next generation high-efficiency solar cells and LEDs, scientists at Los Alamos National Laboratory and their partners are creating...
Silicon nanosheets are thin, two-dimensional layers with exceptional optoelectronic properties very similar to those of graphene. Albeit, the nanosheets are less stable. Now researchers at the Technical University of Munich (TUM) have, for the first time ever, produced a composite material combining silicon nanosheets and a polymer that is both UV-resistant and easy to process. This brings the scientists a significant step closer to industrial applications like flexible displays and photosensors.
Silicon nanosheets are thin, two-dimensional layers with exceptional optoelectronic properties very similar to those of graphene. Albeit, the nanosheets are...
Enzymes behave differently in a test tube compared with the molecular scrum of a living cell. Chemists from the University of Basel have now been able to simulate these confined natural conditions in artificial vesicles for the first time. As reported in the academic journal Small, the results are offering better insight into the development of nanoreactors and artificial organelles.
Enzymes behave differently in a test tube compared with the molecular scrum of a living cell. Chemists from the University of Basel have now been able to...
20.03.2017 | Event News
14.03.2017 | Event News
07.03.2017 | Event News
27.03.2017 | Health and Medicine
27.03.2017 | Life Sciences
27.03.2017 | Earth Sciences