Requirement of nuclear factor-κB in angiotensin II- and isoproterenol-induced cardiac hypertrophy in vivo

Christian Freund, Ruth Schmidt-Ullrich, Anthony Baurand, Sandra Dunger, Wolfgang Schneider, Peter Loser, Amina El-Jamali, Rainer Dietz, Claus Scheidereit, Martin W. Bergmann

Research output: Contribution to journalArticlepeer-review

155 Scopus citations

Abstract

Background - In vitro experiments have proposed a role of nuclear factor-κB (NF-κB), 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-κB super-repressor IκBαΔN (ΔNMHC) using the Cre/lox technique. ΔNMHC 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; ΔNMHC plus Ang II, X1.1±0.1 versus sham; P<0.05; n≥9), heart weight, and histological analysis. Real-time reverse-transcriptase polymerase chain reaction showed significantly reduced expression of hypertrophy markers β-myosin heavy chain and atrial natriuretic peptide in Ang II-treated ΔNMHC 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-κB 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-κB response of cardiomyocytes. Finally, results from in vitro and in vivo experiments suggest a role for NF-κB in the regulation of prohypertrophic interleukin-6 receptor gp130 on mRNA levels. Conclusions - These results indicate that targeted inhibition of NF-κB in cardiomyocytes in vivo is sufficient to impair Ang II- and isoproterenol-induced hypertrophy without increasing the susceptibility to apoptosis.

Original languageEnglish (US)
Pages (from-to)2319-2325
Number of pages7
JournalCirculation
Volume111
Issue number18
DOIs
StatePublished - May 10 2005
Externally publishedYes

Keywords

  • Angiotensin
  • Genes
  • Hypertrophy
  • Myocytes
  • Nuclear factor-κB

ASJC Scopus subject areas

  • Cardiology and Cardiovascular Medicine
  • Physiology (medical)

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