Requirement of nuclear factor-kappaB in angiotensin II- and isoproterenol-induced cardiac hypertrophy in vivo.
BACKGROUND
In vitro experiments have proposed a role of nuclear factor-kappaB (NF-kappaB), 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.


RESULTS
We have generated mice with cardiomyocyte-restricted expression of the NF-kappaB super-repressor IkappaBalphaDeltaN (DeltaN(MHC)) using the Cre/lox technique. DeltaN(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; DeltaN(MHC) plus Ang II, x1.1+/-0.1 versus sham; P<0.05; n> or =9), heart weight, and histological analysis. Real-time reverse-transcriptase polymerase chain reaction showed significantly reduced expression of hypertrophy markers beta-myosin heavy chain and atrial natriuretic peptide in Ang II-treated DeltaN(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-kappaB 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-kappaB response of cardiomyocytes. Finally, results from in vitro and in vivo experiments suggest a role for NF-kappaB in the regulation of prohypertrophic interleukin-6 receptor gp130 on mRNA levels.


CONCLUSIONS
These results indicate that targeted inhibition of NF-kappaB in cardiomyocytes in vivo is sufficient to impair Ang II- and isoproterenol-induced hypertrophy without increasing the susceptibility to apoptosis.
Freund
Christian
C
Franz-Volhard Clinic, Department of Cardiology, HELIOS Klinikum-Berlin, Charité Campus Berlin-Buch, Berlin, Germany.
Schmidt-Ullrich
Ruth
R
Baurand
Anthony
A
Dunger
Sandra
S
Schneider
Wolfgang
W
Loser
Peter
P
El-Jamali
Amina
A
Dietz
Rainer
R
Scheidereit
Claus
C
Bergmann
Martin W
MW
D000804:Angiotensin II / Q000494:pharmacology*; D000818:Animals; D017209:Apoptosis / Q000187:drug effects; D006332:Cardiomegaly / Q000139:chemically induced / Q000209:etiology* / Q000628:therapy; D020672:I-kappa B Proteins / Q000235:genetics; D015850:Interleukin-6 / Q000494:pharmacology; D007545:Isoproterenol / Q000009:adverse effects*; D051379:Mice; D032383:Myocytes, Cardiac / Q000166:cytology / Q000378:metabolism; D000072000:NF-KappaB Inhibitor alpha; D016328:NF-kappa B / Q000037:antagonists & inhibitors / Q000502:physiology*; D019947:Receptors, Interleukin-6 / Q000378:metabolism
D020672:I-kappa B Proteins; D015850:Interleukin-6; D016328:NF-kappa B; C000606205:Nfkbia protein, mouse; C000606206:Nfkbia protein, rat; D019947:Receptors, Interleukin-6; D000804:Angiotensin II; D000072000:NF-KappaB Inhibitor alpha; D007545:Isoproterenol