Published Online
on May 3, 2005

A more recent version of this article appeared on May 10, 2005

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Submitted on June 19, 2004
Revised on November 24, 2004
Accepted on December 23, 2004

Requirement of Nuclear Factor-B 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, and 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.

^* To whom correspondence should be addressed. E-mail: M.Bergmann{at}mdc-berlin.de.

Background--In vitro experiments have proposed a role of nuclear factor-B (NF-B), a transcription factor, in cardiomyocyte hypertrophy and protection against apoptosis. Currently, the net effect on cardiac remodeling in vivo under common stress stimuli is unclear.

Methods and Results--We have generated mice with cardiomyocyte-restricted expression of the NF-B super-repressor IBN (N^MHC) using the Cre/lox technique. N^MHC mice displayed an attenuated hypertrophic response compared with control mice on infusion of angiotensin II (Ang II) or isoproterenol by micro-osmotic pumps, as determined by echocardiography (left ventricular wall dimensions: control plus Ang II, x1.5±0.1 versus sham; N^MHC plus Ang II, x1.1±0.1 versus sham; P<0.05; n9), heart weight, and histological analysis. Real-time reverse-transcriptase polymerase chain reaction showed significantly reduced expression of hypertrophy markers -myosin heavy chain and atrial natriuretic peptide in Ang II-treated N^MHC mice (P<0.05 versus control plus Ang II; n=4). Neither cardiomyocyte apoptosis nor left ventricular dilatation was observed. In cultured adult rat cardiomyocytes, NF-B DNA binding activity was increased by both Ang II- and interleukin-6-related cytokines. The latter are known to be released by cardiac fibroblasts on Ang II stimulation and thus could locally increase the NF-B response of cardiomyocytes. Finally, results from in vitro and in vivo experiments suggest a role for NF-B in the regulation of prohypertrophic interleukin-6 receptor gp130 on mRNA levels.

Conclusions--These results indicate that targeted inhibition of NF-B in cardiomyocytes in vivo is sufficient to impair Ang II- and isoproterenol-induced hypertrophy without increasing the susceptibility to apoptosis.

Key words: angiotensin • genes • hypertrophy • myocytes • nuclear factor-B

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