Interferon-γ causes cardiac myocyte atrophy via selective degradation of myosin heavy chain in a model of chronic myocarditis.
Interferon-γ (IFN-γ), a proinflammatory cytokine, has been implicated in the pathogenesis of a number of forms of heart disease including myocarditis and congestive heart failure. In fact, overexpression of IFN-γ in mice causes dilated cardiomyopathy. However, the direct effects of IFN-γ on cardiac myocytes and the mechanism by which it causes cardiac dysfunction have not been described. Here, we present the molecular pathology of IFN-γ exposure and its effect on myofibrillar proteins in isolated neonatal rat ventricular myocytes. Treatment with IFN-γ caused cardiac myocyte atrophy attributable to a specific decrease in myosin heavy chain protein. This selective degradation of myosin heavy chain was not accompanied by a decrease in total protein synthesis or by an increase in total protein degradation. IFN-γ increased both proteasome and immunoproteasome activity in cardiac myocytes and their inhibition blocked myosin heavy chain loss and myocyte atrophy, whereas inhibition of the lysosome or autophagosome did not. Collectively, these results provide a mechanism by which IFN-γ causes cardiac pathology in the setting of chronic inflammatory diseases.
Department of Molecular, Cellular, and Developmental Biology & BioFrontiers Institute, University of Colorado at Boulder, CO 80309, USA.
Pippa F
PF
Cosper
Pamela A
PA
Harvey
Leslie A
LA
Leinwand
D000818:Animals; D000831:Animals, Newborn; D001284:Atrophy / Q000378:metabolism / Q000473:pathology; D002908:Chronic Disease; D004195:Disease Models, Animal; D006352:Heart Ventricles / Q000473:pathology; D007371:Interferon-gamma / Q000009:adverse effects*; D008247:Lysosomes / Q000187:drug effects / Q000378:metabolism; D051379:Mice; D009205:Myocarditis / Q000378:metabolism* / Q000473:pathology*; D032383:Myocytes, Cardiac / Q000187:drug effects / Q000378:metabolism* / Q000473:pathology*; D018995:Myosin Heavy Chains / Q000378:metabolism*; D010588:Phagosomes / Q000187:drug effects / Q000378:metabolism; D046988:Proteasome Endopeptidase Complex / Q000276:immunology / Q000378:metabolism; D014176:Protein Biosynthesis / Q000187:drug effects; D059748:Proteolysis / Q000187:drug effects; D051381:Rats; D025801:Ubiquitin / Q000378:metabolism
D025801:Ubiquitin; D007371:Interferon-gamma; D046988:Proteasome Endopeptidase Complex; D018995:Myosin Heavy Chains