Proteasome functional insufficiency activates the calcineurin–NFAT pathway in cardiomyocytes and promotes maladaptive remodelling of stressed mouse hearts
Open Access
- 2 July 2010
- journal article
- research article
- Published by Oxford University Press (OUP) in Cardiovascular Research
- Vol. 88 (3), 424-433
- https://doi.org/10.1093/cvr/cvq217
Abstract
Proteasome functional insufficiency (PFI) may play an important role in the progression of congestive heart failure but the underlying molecular mechanism is poorly understood. Calcineurin and nuclear factor of activated T-cells (NFAT) are degraded by the proteasome, and the calcineurin–NFAT pathway mediates cardiac remodelling. The present study examined the hypothesis that PFI activates the calcineurin–NFAT pathway and promotes maladaptive remodelling of the heart. Using a reporter gene assay, we found that pharmacological inhibition of 20S proteasomes stimulated NFAT transactivation in both mouse hearts and cultured adult mouse cardiomyocytes. Proteasome inhibition stimulated NFAT nuclear translocation in a calcineurin-dependent manner and led to a maladaptive cell shape change in cultured neonatal rat ventricular myocytes. Proteasome inhibition facilitated left ventricular dilatation and functional decompensation and increased fatality in mice with aortic constriction while causing cardiac hypertrophy in the sham surgery group. It was further revealed that both calcineurin protein levels and NFAT transactivation were markedly increased in the mouse hearts with desmin-related cardiomyopathy and severe PFI. Expression of an aggregation-prone mutant desmin also directly increased calcineurin protein levels in cultured cardiomyocytes. The calcineurin–NFAT pathway in the heart can be activated by proteasome inhibition and is activated in the heart of a mouse model of desmin-related cardiomyopathy that is characterized by severe PFI. The interplay between PFI and the calcineurin–NFAT pathway may contribute to the pathological remodelling of cardiomyocytes characteristic of congestive heart failure.Keywords
This publication has 43 references indexed in Scilit:
- Calcineurin/NFAT Coupling Participates in Pathological, but not Physiological, Cardiac HypertrophyCirculation Research, 2004
- Phase I Trial of the Proteasome Inhibitor PS-341 in Patients With Refractory Hematologic MalignanciesJournal of Clinical Oncology, 2002
- Enhanced myocyte contractility and Ca2+ handling in a calcineurin transgenic model of heart failure.Cardiovascular Research, 2002
- Capacitative Calcium Entry Contributes to Nuclear Factor of Activated T-cells Nuclear Translocation and Hypertrophy in CardiomyocytesJournal of Biological Chemistry, 2002
- Expression of R120G–αB-Crystallin Causes Aberrant Desmin and αB-Crystallin Aggregation and Cardiomyopathy in MiceCirculation Research, 2001
- Mouse Model of Desmin-Related CardiomyopathyCirculation, 2001
- Differential Activation of Signal Transduction Pathways in Human Hearts With Hypertrophy Versus Advanced Heart FailureCirculation, 2001
- Culture and adenoviral infection of adult mouse cardiac myocytes: methods for cellular genetic physiologyAmerican Journal of Physiology-Heart and Circulatory Physiology, 2000
- Desmin Myopathy, a Skeletal Myopathy with Cardiomyopathy Caused by Mutations in the Desmin GeneThe New England Journal of Medicine, 2000
- Targeted inhibition of calcineurin prevents agonist-induced cardiomyocyte hypertrophyProceedings of the National Academy of Sciences of the United States of America, 2000