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 language | English (US) |
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Pages (from-to) | 2319-2325 |
Number of pages | 7 |
Journal | Circulation |
Volume | 111 |
Issue number | 18 |
DOIs | |
State | Published - May 10 2005 |
Keywords
- Angiotensin
- Genes
- Hypertrophy
- Myocytes
- Nuclear factor-κB
ASJC Scopus subject areas
- Cardiology and Cardiovascular Medicine
- Physiology (medical)