Cardiomyocyte-specific IκB kinase (IKK)/NF-κB activation induces reversible inflammatory cardiomyopathy and heart failure.

Abstract

Inflammation is a major factor in heart disease. IκB kinase (IKK) and its downstream target NF-κB are regulators of inflammation and are activated in cardiac disorders, but their precise contributions and targets are unclear. We analyzed IKK/NF-κB function in the heart by a gain-of-function approach, generating an inducible transgenic mouse model with cardiomyocyte-specific expression of constitutively active IKK2. In adult animals, IKK2 activation led to inflammatory dilated cardiomyopathy and heart failure. Transgenic hearts showed infiltration with CD11b(+) cells, fibrosis, fetal reprogramming, and atrophy of myocytes with strong constitutively active IKK2 expression. Upon transgene inactivation, the disease was reversible even at an advanced stage. IKK-induced cardiomyopathy was dependent on NF-κB activation, as in vivo expression of IκBα superrepressor, an inhibitor of NF-κB, prevented the development of disease. Gene expression and proteomic analyses revealed enhanced expression of inflammatory cytokines, and an IFN type I signature with activation of the IFN-stimulated gene 15 (ISG15) pathway. In that respect, IKK-induced cardiomyopathy resembled Coxsackievirus-induced myocarditis, during which the NF-κB and ISG15 pathways were also activated. Vice versa, in cardiomyocytes lacking the regulatory subunit of IKK (IKKγ/NEMO), the induction of ISG15 was attenuated. We conclude that IKK/NF-κB activation in cardiomyocytes is sufficient to cause cardiomyopathy and heart failure by inducing an excessive inflammatory response and myocyte atrophy.

• Authors: Harald J Maier, Tobias G Schips, Astrid Wietelmann, Marcus Krüger, Cornelia Brunner, Martina Sauter, Karin Klingel, Thomas Böttger, Thomas Braun, Thomas Wirth
• Journal: Proceedings of the National Academy of Sciences of the United States of America (Proc Natl Acad Sci U S A) Vol. 109 Issue 29 Pg. 11794-9 (Jul 17 2012) ISSN: 1091-6490 [Electronic] United States
• PMID: 22753500 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)

Chemical References

• CD11b Antigen
• I-kappa B Proteins
• NF-kappa B
• Nfkbia protein, mouse
• NF-KappaB Inhibitor alpha
• I-kappa B Kinase
• Ikbkb protein, mouse

Topics

• Analysis of Variance
• Animals
• Blotting, Western
• CD11b Antigen (metabolism)
• Cardiomyopathies (enzymology, etiology, pathology)
• Electrophoretic Mobility Shift Assay
• Enzyme Activation (physiology)
• Gene Expression Profiling
• Heart Failure (enzymology, etiology, pathology)
• Histological Techniques
• I-kappa B Kinase (metabolism)
• I-kappa B Proteins (metabolism)
• Luminescent Measurements
• Mice
• Mice, Transgenic
• Microscopy, Fluorescence
• Myocytes, Cardiac (enzymology)
• NF-KappaB Inhibitor alpha
• NF-kappa B (metabolism)