Cardiovascular Research 2005 67(4):689-698; doi:10.1016/j.cardiores.2005.04.030
Copyright © 2005, European Society of Cardiology
Blockade of NF-
B ameliorates myocardial hypertrophy in response to chronic infusion of angiotensin II
Department of Cardiovascular Medicine, Kyushu University Graduate School of Medical Sciences, 3-1-1 Maidashi, Higashi-ku, Fukuoka 812-8582, Japan
* Corresponding author. Tel.: +81 92 642 5360; fax: +81 92 642 5374. Email address: kubotat{at}cardiol.med.kyushu-u.ac.jp
Objective: Nuclear factor (NF)-
B is a key transcription factor that regulates inflammatory processes. In the present study, we assessed the hypothesis that blockade of NF-B may ameliorate ventricular hypertrophy in response to chronic infusion of angiotensin II.
Methods: Mice with targeted disruption of the p50 subunit of NF-B (KO) were used to block the activation of NF-B. Male KO and age-matched wild-type (WT) mice were chronically infused with angiotensin II at the rate of 0.2 (low dose) or 2 µg/kg/min (high dose) for 4 weeks.
Results: High- but not low-dose angiotensin II significantly increased systemic blood pressure and left ventricular weight in WT mice. In contrast, although the pressor response was slightly but significantly augmented, the hypertrophic effect of angiotensin II was significantly attenuated in KO mice. The attenuated hypertrophic responsiveness was confirmed histologically (cross-sectional area) and transcriptionally (atrial natriuretic peptide). Echocardiography revealed no evidence of cardiac dysfunction in angiotensin II-treated KO mice. Although phosphorylation of MAPKs, including ERK, JNK, or p38-MAPK, was not affected after 4 weeks of angiotensin II treatment in WT mice, phosphorylation of JNK was specifically abrogated in KO mice. Angiotensin II increased myocardial expression of proinflammatory cytokines and chemokines in WT mice, while expression of TNF-
and RANTES was paradoxically augmented in KO mice.
Conclusion: Blockade of NF-B activation attenuated myocardial hypertrophy without deteriorating cardiac function. NF-B may play an important role in cardiac hypertrophy and remodeling besides promoting inflammation.
KEYWORDS Angiotensin; Cytokines; Hypertrophy; MAP kinase; Nuclear factor-B; Cardiac remodeling
Time for primary review 24 days
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