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Selective changes in DNA binding activity of transcription factors in UM-X7.1 cardiomyopathic hamsters
R Ambra1, P Di Nardo, C Fantini
1Free Radicals Research Group, National Institute for Food and Nutrition Research, via Ardeatina 546, 00178, Rome, Italy. ambra@inran.it
Insights
Hamster cardiomyopathy involves delta-sarcoglycan loss, impacting heart function. This study reveals altered transcription factor activity, specifically NF-AT3 and CREB, offering new insights into hereditary cardiomyopathy mechanisms.
Area of Science:
- Cardiology
- Molecular Biology
- Genetics
Background:
- UM-X7.1 hamsters (CH) serve as a model for human cardiomyopathy.
- CH exhibit delta-sarcoglycan loss, leading to myocardium remodeling and reduced heart function.
- Molecular mechanisms of CH pathology, despite known redox and calcium imbalances, remain largely unknown.
Purpose of the Study:
- Investigate molecular mechanisms underlying hereditary cardiomyopathy in CH.
- Analyze the role of transcription factors in CH pathogenesis.
- Identify novel regulatory pathways in cardiac dysfunction.
Main Methods:
- Compared DNA binding activity of transcription factors in CH vs. normal hamster ventricles.
- Utilized Western blot to confirm protein levels.
- Focused on redox-related (NF-kappaB, Sp1, AP-1, AP-2) and calcium-dependent (NF-AT3, CREB) factors.
Main Results:
- No significant difference in DNA binding activity of redox-related transcription factors.
- Increased DNA binding activity of NF-AT3 in CH ventricles.
- Decreased DNA binding activity and levels of CREB in CH ventricles, suggesting novel regulation.
Conclusions:
- Altered transcription factor activity, particularly NF-AT3 and CREB, contributes to CH pathogenesis.
- Findings provide insights into the molecular mechanisms of hamster hereditary cardiomyopathy.
- Results align with studies on related transgenic mouse models.
Abstract:
UM-X7.1 hamsters (CH) are considered a representative model for human cardiomyopathy. CH display the loss of the cytoskeletal delta-sarcoglycan protein, associated with myocardium remodeling and fatal reduction of heart functional efficiency. Even though altered redox balance and calcium homeostasis have already been reported to affect cardiomyocyte function, the molecular mechanisms underlying this pathology are largely unknown. We found no significant differences in DNA binding activity of redox-related (NF-kappaB, Sp1, AP-1 and AP-2) transcription factors in heart ventricles of 90 day-old CH, compared to normal animals. On the other hand, DNA binding activity of calcium-dependent transcription factors NF-AT3 and CREB were increased and decreased respectively in CH vs. normal ventricles. Western blot experiments confirmed the down regulation of CREB levels and suggest a novel regulation mechanism for this transcription factor in the heart. Our results are consistent with recent studies on NF-AT3, GATA4 and CREB transgenic mice, and provide clues for the comprehension of pathogenetic mechanisms of hamster hereditary cardiomyopathy.