title: 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: Institute of Physiological Chemistry,  University of Ulm, 89081 Ulm,  Germany.
authors: Harald J
authors: HJ
authors: Maier
authors: Tobias G
authors: TG
authors: Schips
authors: Astrid
authors: A
authors: Wietelmann
authors: Marcus
authors: M
authors: Krüger
authors: Cornelia
authors: C
authors: Brunner
authors: Martina
authors: M
authors: Sauter
authors: Karin
authors: K
authors: Klingel
authors: Thomas
authors: T
authors: Böttger
authors: Thomas
authors: T
authors: Braun
authors: Thomas
authors: T
authors: Wirth
mesh_terms: D000704:Analysis of Variance; D000818:Animals; D015153:Blotting, Western; D039481:CD11b Antigen / Q000378:metabolism; D009202:Cardiomyopathies / Q000201:enzymology / Q000209:etiology* / Q000473:pathology; D024202:Electrophoretic Mobility Shift Assay; D004789:Enzyme Activation / Q000502:physiology*; D020869:Gene Expression Profiling; D006333:Heart Failure / Q000201:enzymology / Q000209:etiology* / Q000473:pathology; D006652:Histological Techniques; D051550:I-kappa B Kinase / Q000378:metabolism*; D020672:I-kappa B Proteins / Q000378:metabolism; D008163:Luminescent Measurements; D051379:Mice; D008822:Mice, Transgenic; D008856:Microscopy, Fluorescence; D032383:Myocytes, Cardiac / Q000201:enzymology*; D000072000:NF-KappaB Inhibitor alpha; D016328:NF-kappa B / Q000378:metabolism*
chemical_list: D039481:CD11b Antigen; D020672:I-kappa B Proteins; D016328:NF-kappa B; C000606205:Nfkbia protein, mouse; D000072000:NF-KappaB Inhibitor alpha; D051550:I-kappa B Kinase; C496562:Ikbkb protein, mouse