Background-In vitro experiments have proposed a role of nuclear factor-kappa B (NF-kappa 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-kappa B super-repressor I kappa B alpha Delta N (Delta N-MHC) using the Cre/lox technique. Delta 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, x 1.5 +/- 0.1 versus sham; Delta N-MHC plus Ang II, x 1.1 +/- 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 beta- myosin heavy chain and atrial natriuretic peptide in Ang II-treated Delta 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-kappa 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-kappa B response of cardiomyocytes. Finally, results from in vitro and in vivo experiments suggest a role for NF-kappa B in the regulation of prohypertrophic interleukin-6 receptor gp130 on mRNA levels. Conclusions-These results indicate that targeted inhibition of NF-kappa B in cardiomyocytes in vivo is sufficient to impair Ang II- and isoproterenol-induced hypertrophy without increasing the susceptibility to apoptosis.
机构:Childrens Hosp, Med Ctr, Div Mol Cardiovasc Biol, Cincinnati, OH 45229 USA
Bueno, OF
Wilkins, BJ
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机构:Childrens Hosp, Med Ctr, Div Mol Cardiovasc Biol, Cincinnati, OH 45229 USA
Wilkins, BJ
Tymitz, KM
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机构:Childrens Hosp, Med Ctr, Div Mol Cardiovasc Biol, Cincinnati, OH 45229 USA
Tymitz, KM
Glascock, BJ
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机构:Childrens Hosp, Med Ctr, Div Mol Cardiovasc Biol, Cincinnati, OH 45229 USA
Glascock, BJ
Kimball, TF
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机构:Childrens Hosp, Med Ctr, Div Mol Cardiovasc Biol, Cincinnati, OH 45229 USA
Kimball, TF
Lorenz, JN
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机构:Childrens Hosp, Med Ctr, Div Mol Cardiovasc Biol, Cincinnati, OH 45229 USA
Lorenz, JN
Molkentin, JD
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机构:
Childrens Hosp, Med Ctr, Div Mol Cardiovasc Biol, Cincinnati, OH 45229 USAChildrens Hosp, Med Ctr, Div Mol Cardiovasc Biol, Cincinnati, OH 45229 USA
机构:Childrens Hosp, Med Ctr, Div Mol Cardiovasc Biol, Cincinnati, OH 45229 USA
Bueno, OF
Wilkins, BJ
论文数: 0引用数: 0
h-index: 0
机构:Childrens Hosp, Med Ctr, Div Mol Cardiovasc Biol, Cincinnati, OH 45229 USA
Wilkins, BJ
Tymitz, KM
论文数: 0引用数: 0
h-index: 0
机构:Childrens Hosp, Med Ctr, Div Mol Cardiovasc Biol, Cincinnati, OH 45229 USA
Tymitz, KM
Glascock, BJ
论文数: 0引用数: 0
h-index: 0
机构:Childrens Hosp, Med Ctr, Div Mol Cardiovasc Biol, Cincinnati, OH 45229 USA
Glascock, BJ
Kimball, TF
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h-index: 0
机构:Childrens Hosp, Med Ctr, Div Mol Cardiovasc Biol, Cincinnati, OH 45229 USA
Kimball, TF
Lorenz, JN
论文数: 0引用数: 0
h-index: 0
机构:Childrens Hosp, Med Ctr, Div Mol Cardiovasc Biol, Cincinnati, OH 45229 USA
Lorenz, JN
Molkentin, JD
论文数: 0引用数: 0
h-index: 0
机构:
Childrens Hosp, Med Ctr, Div Mol Cardiovasc Biol, Cincinnati, OH 45229 USAChildrens Hosp, Med Ctr, Div Mol Cardiovasc Biol, Cincinnati, OH 45229 USA