Blockade of NF-kappaB ameliorates myocardial hypertrophy in response to chronic infusion of angiotensin II.

Abstract

OBJECTIVE:

Nuclear factor (NF)-kappaB is a key transcription factor that regulates inflammatory processes. In the present study, we assessed the hypothesis that blockade of NF-kappaB may ameliorate ventricular hypertrophy in response to chronic infusion of angiotensin II.

METHODS:

Mice with targeted disruption of the p50 subunit of NF-kappaB (KO) were used to block the activation of NF-kappaB. 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 microg/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-alpha and RANTES was paradoxically augmented in KO mice.

CONCLUSION:

Blockade of NF-kappaB activation attenuated myocardial hypertrophy without deteriorating cardiac function. NF-kappaB may play an important role in cardiac hypertrophy and remodeling besides promoting inflammation.

• Authors: Shunichi Kawano, Toru Kubota, Yoshiya Monden, Natsumi Kawamura, Hiroyuki Tsutsui, Akira Takeshita, Kenji Sunagawa
• Journal: Cardiovascular research (Cardiovasc Res) Vol. 67 Issue 4 Pg. 689-98 (Sep 01 2005) ISSN: 0008-6363 [Print] England
• PMID: 15921667 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)

Chemical References

• Chemokine CCL5
• NF-kappa B
• RNA, Messenger
• Receptors, Angiotensin
• Tumor Necrosis Factor-alpha
• Angiotensin II
• Mitogen-Activated Protein Kinases
• MAP Kinase Kinase 4

Topics

• Angiotensin II (pharmacology)
• Animals
• Chemokine CCL5 (metabolism)
• Dose-Response Relationship, Drug
• Echocardiography
• Electrophoretic Mobility Shift Assay
• Hypertrophy, Left Ventricular (metabolism)
• Immunohistochemistry (methods)
• Infusions, Intravenous
• MAP Kinase Kinase 4 (metabolism)
• Male
• Mice
• Mice, Knockout
• Mitogen-Activated Protein Kinases (metabolism)
• Models, Animal
• Myocardium (metabolism)
• NF-kappa B (physiology)
• RNA, Messenger (analysis)
• Receptors, Angiotensin (genetics)
• Reverse Transcriptase Polymerase Chain Reaction
• Tumor Necrosis Factor-alpha (metabolism)
• Ventricular Remodeling