AlphaB-crystallin modulates protein aggregation of abnormal desmin
| Autor: | Jeffrey Robbins, Faqian Li, Raisa Klevitsky, Joseph W. Glasford, Xuejun Wang, Wei Huang |
|---|---|
| Rok vydání: | 2003 |
| Předmět: |
medicine.medical_specialty
Heterozygote Physiology Macromolecular Substances Mice Transgenic macromolecular substances Biology Protein aggregation Protein degradation Kidney Transfection Desmin Mice Downregulation and upregulation Heat shock protein Internal medicine medicine Animals Humans RNA Messenger Intermediate filament Cells Cultured Crosses Genetic Myocardium HEK 293 cells Body Weight Kidney metabolism alpha-Crystallin B Chain Organ Size Cell biology Survival Rate Endocrinology Mutation Disease Progression Cardiology and Cardiovascular Medicine Cardiomyopathies |
| Zdroj: | Circulation research. 93(10) |
| ISSN: | 1524-4571 |
| Popis: | αB-crystallin (CryAB) is the most abundant small heat shock protein in the heart. Upregulation of CryAB in desmin-related myopathy and its downregulation in end-stage congestive heart failure have both been reported. We previously demonstrated via cardiac-specific transgenesis that modest increases in normal CryAB are not detrimental to the heart, whereas expression of the R120G mutation of CryAB caused a desminopathy. It is generally believed that CryAB plays an important role in protecting the intermediate filaments, but the underlying mechanism is unclear. We hypothesized that CryAB protects the desmin filaments via preventing abnormal desmin protein from aggregating adversely. To test this hypothesis in vivo, mice expressing a desmin mutation that causes a desmin-related cardiomyopathy (D7) were bred into the R120G-CryAB transgenic (TG) background to examine the accumulation and aberrant aggregation of desmin protein. Despite lower mRNA expression of D7-des than in the D7-des TG hearts, the double-TG myocardium exhibited significantly higher desmin protein levels and dramatically more aberrant desmin aggregates than the D7-des TG hearts. The double-TG mice displayed a significantly stronger cardiac hypertrophic response, with the mice dying of congestive heart failure before 7 weeks. To explore the ability of wild-type (WT) CryAB to protect against mutant desmin, a desmin mutant was expressed in both the conventional and WT-CryAB stably transfected HEK cells. Significantly less aberrant desmin aggregation was observed in the WT-CryAB–overexpressing cells than in the HEK cells. The results suggest that CryAB modulates abnormal desmin aggregation and can serve a cardioprotective role. |
| Databáze: | OpenAIRE |
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