| First Author | Maier HJ | Year | 2012 |
| Journal | Proc Natl Acad Sci U S A | Volume | 109 |
| Issue | 29 | Pages | 11794-9 |
| PubMed ID | 22753500 | Mgi Jnum | J:186490 |
| Mgi Id | MGI:5432435 | Doi | 10.1073/pnas.1116584109 |
| Citation | Maier HJ, et al. (2012) Cardiomyocyte-specific IkappaB kinase (IKK)/NF-kappaB activation induces reversible inflammatory cardiomyopathy and heart failure. Proc Natl Acad Sci U S A 109(29):11794-9 |
| abstractText | Inflammation is a major factor in heart disease. IkappaB kinase (IKK) and its downstream target NF-kappaB are regulators of inflammation and are activated in cardiac disorders, but their precise contributions and targets are unclear. We analyzed IKK/NF-kappaB 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-kappaB activation, as in vivo expression of IkappaBalpha superrepressor, an inhibitor of NF-kappaB, 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-kappaB and ISG15 pathways were also activated. Vice versa, in cardiomyocytes lacking the regulatory subunit of IKK (IKKgamma/NEMO), the induction of ISG15 was attenuated. We conclude that IKK/NF-kappaB activation in cardiomyocytes is sufficient to cause cardiomyopathy and heart failure by inducing an excessive inflammatory response and myocyte atrophy. |
