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Hypertension is one of the main causes for cardiac hypertrophy. According to the American Framingham study, about one per cent of the population suffers from this disease which impairs the heart severely over time and is one of the main causes for breathing difficulties and disability in the elderly. Now, researchers and clinicians from the Franz Volhard Klinik (FVK) for Cardiovascular Diseases (Helios Klinikum Berlin-Buch/Charité Berlin-Buch Campus University Medicine Berlin) and the Max Delbrück Center for Molecular Medicine (MDC) Berlin-Buch in Germany were able to show that blocking the gene regulator, nuclear factor (NF) kappaB, is sufficient to protect the heart from being damaged in mice with hypertension. The findings of Christian Freund and Dr. Martin Bergmann (FVK) as well as Dr. Ruth Schmidt-Ullrich and Prof. Claus Scheidereit (MDC) were published in the latest issue of the American journal Circulation on May 10, 2005 (www.circulationaha.org). The MDC, a national research institution of the Helmholtz-Association, financed this research as part of its special programme which fosters cooperation between basic researchers and clinicians. Next, researchers and clinicians plan to conduct clinical trials to find out if NF-kappaB inhibitors, currently being tested in inflammatory lung and bowel diseases, will also prove effective in cardiac hypertrophy.
The heart of patients suffering from cardiac hypertrophy is too weak to pump the blood through the body and supply it sufficiently with blood and oxygen. As a result, the patients are tired, weary, and can hardly breathe. The heart muscle cells try to compensate for this reduced pumping by developing new active muscle fibers. Because heart muscle cells are no longer able to divide, they get larger instead, a process physicians call hypertrophy, resulting in the thickening of the heart muscle wall as well as the stiffening of the left heart ventricle. This process increases the breathing difficulties for the patient under physical stress because the blood stream circulating between the lungs and the heart is disturbed. Therefore, these self-repairing processes no longer work, and the disease gets worse, if left untreated. The latest data from the mouse model however, show that the gene regulator NF-kappaB plays a crucial role in regulating the enlargement of heart muscle cells. Blocking NF-kappa-B probably will suffice to break the vicious circle of reduced pumping capability and hypertrophy and, thus, prevent the development of cardiac hypertrophy.
NF-kappaB has been identified as a gene regulator that is involved in asthma and other inflammatory diseases. Data suggest that the reason steroids are so effective in treating inflammatory diseases is because they block this gene regulator. In 1996, Prof. Scheidereit and the oncologist Prof. Bernd Dörken (MDC and Charité) showed that NF-kappaB triggers the malignant cell growth in Hodgkin`s lymphoma. As a result of their work in elucidating the function of NF-kappaB in Hodgkin's lymphoma, they were recently awarded the German Cancer Award.
As researchers have found out in recent years, NF-kappaB plays a universal role in embryonic development as well as in various diseases. In the healthy organism, NF-kappaB regulates the reaction of the immune system as well as the development of the hair, teeth, bones, and specific glands. At the same time, NF-kappaB is important for the development of diseases, not only Hodgkin's lymphoma, but also various leukaemias and other tumours, inflammatory diseases (e.g., polyarthritis, Morbus Crohn, asthma), cardiovascular diseases (e.g., arteriosclerosis), and, as reported here, cardiac hypertrophy.
Normally, NF-kappaB lies dormant in the cytoplasm hooked to a binding protein (IkappaB-alpha). The gene regulator is activated by a chemical process called phosphorylation, which destroys the binding protein. NF-kappaB, now released, migrates into the cell nucleus to turn on specific genes which can cause disease. When the binding protein is mutated, it cannot be destroyed by the phosphorylation process and NF-kappaB is unable to get into the cell nucleus. This blockade prevents the heart muscle cells from enlarging. "It is crucial that we have been able to detect this process in the living organism", Dr. Bergmann, who also conducts research at the MDC as a Helmholtz-Fellow, explains. "It is often extremely difficult to get high blood pressure under control pharmacologically. Based on our new findings, it is perhaps possible to develop new strategies, to prevent severe heart damage in patients with hypertension, even when their blood pressure cannot be perfectly controlled," the cardiologist hopes.
*Requirement of Nuclear Factor-kappaB in Angiotensin II and Isoproterenol-Induced Cardiac Hypertrophy In Vivo
Christian Freund, MSc; Ruth Schmidt-Ullrich, PhD, Anthony Baurand, PhD; Sandra Dunger, MSc; Wolfgang Schneider, MD; Peter Loser, PhD; Amina El-Jamali, PhD; Rainer Dietz, MD, PhD; Claus Scheidereit, PhD; Martin W. Bergmann, MD
From the Franz-Volhard Clinic, Department of Cardiology, HELIOS Klinikum-Berlin, Charité Campus Berlin-Buch (C.F., S.D., W.S., R.D., M.W.B.); Robert Koch Institut (P.L.); and Max Delbrück Center for Molecular Medicine (R.S.-U., A.B., A.E.-J., C.S.), Berlin, Germany.
Correspondence to Martin W. Bergmann, MD, Franz Volhard Clinic, Charité Campus Buch, Wiltbergstr 50, 13125 Berlin, Germany (E-mail M.Bergmann@mdc-berlin.de), or to Dr Ruth Schmidt-Ullrich, PhD, Max Delbrück Center for Molecular Medicine, Robert-Rössle-Str 10, 13092 Berlin, Germany (E-mail rschmidt@mdc-berlin.de).
© 2005 American Heart Association, Inc.
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Max Delbrück Center for Molecular Medicine(MDC) Berlin-Buch
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