Requirement of Nuclear Factor-kappaB in Angiotensin II and Isoproterenol-Induced Cardiac Hypertrophy In Vivo

The causes and effects of cardiac hypertrophy have been extensively documented, but the underlying molecular mechanisms that link the cell changes to molecular signals and specific cardiac signaling pathways, remain poorly understood. Now, a joint group of MDC researchers and clinicians from the Franz Volhard Clinic (FVK) for Cardiovascular Diseases has shown that blocking the gene regulator, nuclear factor (NF) kappaB, is sufficient to protect the heart from being damaged in hypertensive mice.

Nuclear factor-kappaB (NF-kappaB), a ubiquitous transcription factor, is known for its role in immunity, inflammation, regulation of cell growth, apoptosis, and embryonal development. Normally, NF-kappaB lies dormant in the cytoplasm due to interaction with its inhibitory proteins, the IkappaBs, which are degraded on stimulation.

The research team studied the in vivo effect of heart-restricted NF-kappaB inhibition in hearts (DeltaN-MHC mice). By using the hypertensive and cardiac hypertrophy stimuli, Ang II and the beta-adrenoceptor agonist isoproterenol (Iso), as a model system for hypertension-induced heart disease, they could show that cardiac NF-kappaB inhibition is sufficient to abrogate cardiac hypertrophy without detectable levels of side effects like i.e. increased apoptosis of cardiac muscle cells.

Thus, researchers suggest that NF-kappaB might be an attractive target to inhibit hypertrophy in hypertension. The findings of Christian Freund (laboratory of Martin Bergmann, FVK), Dr. Ruth Schmidt-Ullrich (laboratory of Claus Scheidereit, MDC), and colleagues have been published in the journal Circulation (Freund, C., R. Schmidt-Ullrich, A. Baurand, S. Dunger, W. Schneider, P. Loser, A. El-Jamali, R. Dietz, C. Scheidereit and M. Bergmann (2005). "Requirement of NF-kappaB in angiotensin II- and isoproterenol-induced cardiac hypertrophy in vivo." Circulation 111: 2319-25). Next, the research-clinical team aims to conduct clinical trials to test if NF-kappaB inhibitors, currently being tested in inflammatory lung and bowel diseases, also prove effective in protecting the heart from end-organ damage in hypertensive patients.

Contact:

Pamela Cohen
p.cohen@mdc-berlin.de
+49 30 9406 2121