Elevated p53 expression is associated with dysregulation of the ubiquitin-proteasome system in dilated cardiomyopathy
| Autor: | Mak Khan, Paul J.R. Barton, Paul C. Evans, Emma J. Birks, Le Anh Luong, Karine Enesa, Huib Ovaa, Tonje Folkvang, Padmini Sarathchandra, Magdi H. Yacoub, Najma Latif, Cesare M. Terracciano |
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| Rok vydání: | 2008 |
| Předmět: |
Adult
Cardiomyopathy Dilated Male medicine.medical_specialty Proteasome Endopeptidase Complex Physiology Poly (ADP-Ribose) Polymerase-1 Caspase 3 Apoptosis DNA Fragmentation Ubiquitin-Specific Peptidase 7 Young Adult Ubiquitin Physiology (medical) Internal medicine Gene expression medicine Humans cardiovascular diseases Caspase Deoxyribonucleases biology Apoptosis Regulator Myocardium Proto-Oncogene Proteins c-mdm2 Middle Aged Molecular biology Caspase 9 Up-Regulation Endocrinology Proteasome biology.protein DNA fragmentation Mdm2 Female Poly(ADP-ribose) Polymerases Tumor Suppressor Protein p53 Cardiology and Cardiovascular Medicine Apoptosis Regulatory Proteins Ubiquitin Thiolesterase |
| Zdroj: | Cardiovascular research. 79(3) |
| ISSN: | 0008-6363 |
| Popis: | Aims The molecular mechanisms that regulate cardiomyocyte apoptosis and their role in human heart failure (HF) are uncertain. Expression of the apoptosis regulator p53 is governed by minute double minute 2 (MDM2), an E3 enzyme that targets p53 for ubiquitination and proteasomal processing, and by the deubiquitinating enzyme, herpesvirus-associated ubiquitin-specific protease (HAUSP), which rescues p53 by removing ubiquitin chains from it. Here, we examined whether elevated expression of p53 was associated with dysregulation of ubiquitin-proteasome system (UPS) components and activation of downstream effectors of apoptosis in human dilated cardiomyopathy (DCM). Methods and results Left ventricular myocardial samples were obtained from patients with DCM (n ¼ 12) or from non-failing (donor) hearts (n ¼ 17). Western blotting and immunohistochemistry revealed that DCM tissues contained elevated levels of p53 and its regulators MDM2 and HAUSP (all P , 0.01) compared with non-failing hearts. DCM tissues also contained elevated levels of polyubiquitinated proteins and possessed enhanced 20S-proteasome chymotrypsin-like activities (P , 0.04) as measured in vitro using a fluorogenic substrate. DCM tissues contained activated caspases-9 and -3 (P , 0.001) and reduced expression of the caspase substrate PARP-1 (P , 0.05). Western blotting and immunohistochemistry revealed that DCM tissues contained elevated expression levels of caspase-3activated DNAse (CAD; P , 0.001), which is a key effector of DNA fragmentation in apoptosis and also contained elevated expression of a potent inhibitor of CAD (ICAD-S; P , 0.01). Conclusion Expression of p53 in human DCM is associated with dysregulation of UPS components, which are known to regulate p53 stability. Elevated p53 expression and caspase activation in DCM was not associated with activation of both CAD and its inhibitor, ICAD-S. Our findings are consistent with the concept that apoptosis may be interrupted and therefore potentially reversible in human HF. |
| Databáze: | OpenAIRE |
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