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Cardiomyocyte-specific I?B kinase (IKK)/NF-?B activation induces reversible inflammatory cardiomyopathy and heart failure.

ABSTRACT: Inflammation is a major factor in heart disease. I?B kinase (IKK) and its downstream target NF-?B are regulators of inflammation and are activated in cardiac disorders, but their precise contributions and targets are unclear. We analyzed IKK/NF-?B 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-?B activation, as in vivo expression of I?B? superrepressor, an inhibitor of NF-?B, 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-?B and ISG15 pathways were also activated. Vice versa, in cardiomyocytes lacking the regulatory subunit of IKK (IKK?/NEMO), the induction of ISG15 was attenuated. We conclude that IKK/NF-?B activation in cardiomyocytes is sufficient to cause cardiomyopathy and heart failure by inducing an excessive inflammatory response and myocyte atrophy.

SUBMITTER: Maier HJ

PROVIDER: S-EPMC3406816 | biostudies-other | 2012 Jul

REPOSITORIES: biostudies-other

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

Maier Harald J HJ Schips Tobias G TG Wietelmann Astrid A Krüger Marcus M Brunner Cornelia C Sauter Martina M Klingel Karin K Böttger Thomas T Braun Thomas T Wirth Thomas T

Proceedings of the National Academy of Sciences of the United States of America 20120702 29

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 ...[more]

PMID: 22753500

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Project description:BACKGROUND:Skeletal muscle myopathy and exercise intolerance are diagnostic hallmarks of heart failure (HF). However, the molecular adaptations of skeletal muscles during dilated cardiomyopathy (DCM)-mediated HF are not completely understood. METHODS:Skeletal muscle structure and function were compared in wild-type (WT) and cardiac myosin binding protein-C null mice (t/t), which develop DCM-induced HF. Cardiac function was examined by echocardiography. Exercise tolerance was measured using a graded maximum treadmill running test. Hindlimb muscle function was assessed in vivo from measurements of plantar flexor strength. Inflammatory status was evaluated from the expression of inflammatory markers and the presence of specific immune cell types in gastrocnemius muscles. Muscle regenerative capacityat days 3, 7, and 14 after eccentric contraction-induced injury was determined from the number of phenotypically new and adult fibers in the gastrocnemius, and functional recovery of plantar flexion torque. RESULTS:t/t mice developed DCM-induced HF in association with profound exercise intolerance, consistent with previous reports. Compared to WT, t/t mouse hearts show significant hypertrophy of the atria and ventricles and reduced fractional shortening, both systolic and diastolic. In parallel, the skeletal muscles of t/t mice exhibit weakness and myopathy. Compared to WT, plantar flexor muscles of t/t null mice produce less peak isometric plantar torque (Po), develop torque more slowly (+?dF/dt), and relax more slowly (-?dF/dt, longer half-relaxation times,1/2RT). Gastrocnemius muscles of t/t mice have a greater number of fibers with smaller diameters and central nuclei. Oxidative fibers, both type I and type IIa, show significantly smaller cross-sectional areas and more central nuclei. These fiber phenotypes suggest ongoing repair and regeneration under homeostatic conditions. In addition, the ability of muscles to recover and regenerate after acute injury is impaired in t/t mice. CONCLUSIONS:Our studies concluded that DCM-induced HF induces a unique skeletal myopathy characterized by decreased muscle strength, atrophy of oxidative fiber types, ongoing inflammation and damage under homeostasis, and impaired regeneration after acute muscle injury. Furthermore, this unique myopathy in DCM-induced HF likely contributes to and exacerbates exercise intolerance. Therefore, efforts to develop therapeutic interventions to treat skeletal myopathy during DCM-induced HF should be considered.

Dataset Information

Cardiomyocyte-specific I?B kinase (IKK)/NF-?B activation induces reversible inflammatory cardiomyopathy and heart failure.

Publications

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

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