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Increased expression of the gene for alpha-interferon-inducible protein in cardiomyopathic hamster heart
E M Denovan-Wright1, G R Ferrier, H A Robertson
1Department of Pharmacology, Faculty of Medicine, Dalhousie University, Halifax, Nova Scotia, B3H 4H7, Canada.
Insights
Cardiomyopathic hamsters with a delta-sarcoglycan gene defect show increased levels of the alpha-interferon-inducible protein p27-h. This occurs before cardiac hypertrophy and heart failure develop, indicating an early molecular change.
Area of Science:
- Genetics
- Molecular Biology
- Cardiovascular Research
Background:
- Cardiomyopathic (CM) hamsters possess a delta-sarcoglycan gene defect.
- This genetic defect causes progressive cardiac necrosis, hypertrophy, and eventual heart failure in CM hamsters.
- Understanding early molecular changes is crucial for deciphering disease progression.
Purpose of the Study:
- To identify novel gene expression changes in the hearts of CM hamsters at various disease stages.
- To investigate the role of specific genes in the pathogenesis of inherited cardiomyopathy.
- To find early molecular markers preceding cardiac dysfunction.
Main Methods:
- Differential display was employed to compare mRNA expression profiles between wild-type and CM hamsters at 30, 60, and 90 days of age.
- A cDNA fragment with sequence similarity to human p27 was identified.
- Quantitative analysis of mRNA levels was performed using techniques like Northern blotting or RT-PCR.
Main Results:
- A 400-bp cDNA homologous to human alpha-interferon-inducible protein (p27) was identified.
- Steady-state levels of the corresponding 570-base mRNA (p27-h) were significantly elevated in CM hamster hearts at 30, 60, and 90 days.
- Increased p27-h expression was observed in cardiac and skeletal muscle of CM hamsters by 60 days, but not in other organs.
Conclusions:
- Inherited delta-sarcoglycan gene disruption in CM hamsters leads to the upregulation of p27-h.
- Elevated p27-h expression precedes the onset of cardiac hypertrophy and heart failure.
- p27-h may serve as an early molecular indicator of cardiomyopathy progression in this model.
Abstract:
Cardiomyopathic (CM) hamsters have a disruption in the delta-sarcoglycan gene which leads to progressive cardiac necrosis by 30 to 40 days of age, hypertrophy by 120 days, and heart failure by 250 days. We used differential display to detect other changes in mRNA levels in 30-, 60-, and 90-day-old wild-type and CM hamsters. We identified a 400-bp cDNA with sequence similarity to the human alpha-interferon-inducible protein (p27). This cDNA annealed with a 570-base mRNA whose steady-state levels were increased in 30-, 60-, and 90-day-old CM compared to wild-type heart. Increased expression of this hamster homolog of p27 (p27-h) was detected in CM hamster cardiac and skeletal muscle at 60 days of age but not in liver, kidney, or brain. Thus, an inherited defect in CM hamsters leads to increased expression of p27-h in advance of the development of hypertrophy and heart failure.