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Cardiovascular Research Advance Access first published online on July 20, 2009
This version [Corrected Proof] published online on August 27, 2009
Cardiovascular Research, doi:10.1093/cvr/cvp237
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Published on behalf of the European Society of Cardiology. All rights reserved. © The Author 2009. For permissions please email: journals.permissions@oxfordjournals.org.

NF-{kappa}B activation is required for adaptive cardiac hypertrophy

Laura Zelarayan1,2, Anke Renger1,2, Claudia Noack1,2, Maria-Patapia Zafiriou1,2, Christina Gehrke1,2, Roel van der Nagel3, Rainer Dietz1,2, Leon de Windt3 and Martin W. Bergmann1,2,*

1 Department of Cardiology, Franz Volhard Klinik, Experimental Clinical Research Center (ECRC), Charité Campus Buch, Berlin, Germany
2 Max Delbrück Center for Molecular Medicine, Berlin, Germany
3 Division of Heart and Lungs, Department of Medical Physiology, University Medical Center Utrecht, Utrecht, The Netherlands

* Corresponding author: Department of Cardiology, Asklepios Clinic St Georg, Hanseatic Heart Center, Lohmühlenstr. 5, 20099 Hamburg, Germany. Tel: +49 40 181885 2450; fax: +49 40 181885 4444.E-mail address: docbergmann{at}mac.com

Aims: We have previously shown that cardiac-specific inhibition of NF-{kappa}B attenuates angiotensin II (AngII)-induced left ventricular (LV) hypertrophy in vivo. We now tested whether NF-{kappa}B inhibition is able to block LV remodelling upon chronic pressure overload and chronic AngII stimulation.

Methods and results: Cardiac-restricted NF-{kappa}B inhibition was achieved by expression of a stabilized I{kappa}B{alpha} mutant (I{kappa}B{alpha}{Delta}N) in cells with an active {alpha}-myosin heavy chain ({alpha}MHC) promoter employing the Cre/lox technique. Upon low-gradient trans-aortic constriction (TAC, gradient 21 ± 3 mmHg), hypertrophy was induced in both male and female control mice after 4 weeks. At this time, LV hypertrophy was blocked in transgenic (TG) male but not female mice with NF-{kappa}B inhibition. Amelioration of LV hypertrophy was associated with activation of NF-{kappa}B by dihydrotestosterone in isolated neonatal cardiomyocytes. LV remodelling was not attenuated by NF-{kappa}B inhibition after 8 weeks TAC, demonstrated by decreased fractional shortening (FS) in both control and TG mice irrespective of gender. Similar results were obtained when TAC was performed with higher gradients (48 ± 4 mmHg). In TG mice, FS dropped to similar low levels over the same time course [FS sham, 29 ± 1% (mean ± SEM); FS control + 14 days TAC, 13 ± 3%; FS TG + 14 days TAC, 9 ± 5%]. Similarly, LV remodelling was accelerated by NF-{kappa}B inhibition in an AngII-dependent genetic heart failure model (AT1-R{alpha}MHC) associated with significantly increased cardiac fibrosis in double AT1-R{alpha}MHC/TG mice.

Conclusion: NF-{kappa}B inhibition attenuates cardiac hypertrophy in a gender-specific manner but does not alter the course of stress-induced LV remodelling, indicating NF-{kappa}B to be required for adaptive cardiac hypertrophy.

KEYWORDS NF-{kappa}B; Hypertrophy; Remodelling; Signal transduction; Apoptosis; Fibrosis; Angiotensin; Hypertension

Time for primary review: 27 days


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