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Phospholamban overexpression in transgenic rabbits
James Scott Pattison1, Jason R Waggoner, Jeanne James
1Division of Molecular Cardiovascular Biology, Cincinnati Children's Hospital Research Foundation, 3333 Burnet Avenue, Cincinnati, OH 45229-3039, USA.
Transgenic Research
|September 21, 2007
Summary
Phospholamban (PLN) is crucial for heart calcium handling. Overexpressing PLN in rabbits, unlike mice, causes severe health issues, indicating species-specific sensitivity and a narrow therapeutic window for heart failure treatments.
Area of Science:
- Cardiovascular Physiology
- Molecular Cardiology
- Genetics
Background:
- Phospholamban (PLN) regulates sarcoplasmic reticulum calcium cycling, impacting cardiac function.
- Therapeutic strategies targeting PLN for heart failure are of significant interest.
- Rodent models may not accurately reflect human cardiac calcium handling due to species differences.
Purpose of the Study:
- To investigate the role of phospholamban in rabbit cardiac function and calcium handling.
- To generate transgenic rabbits overexpressing phospholamban to assess its physiological impact.
- To compare phospholamban's effects in rabbits versus mice.
Main Methods:
- Generation of transgenic rabbits overexpressing wild-type phospholamban in cardiomyocytes and skeletal muscle.
- Phenotypic analysis of high-PLN expressing rabbits, including viability, skeletal muscle, and cardiac assessments.
- Biochemical and functional analyses of viable transgenic rabbits, including PLN protein levels, cardiac pathology, and sarcoplasmic reticulum calcium uptake.
Main Results:
- High PLN overexpression led to non-viability, severe skeletal muscle wasting, cardiac pathology, and premature death in rabbits.
- A viable transgenic line showed a 30% increase in cardiac PLN protein levels.
- Transgenic rabbits exhibited reduced SR-calcium affinity but maintained normal cardiac function and beta-adrenergic response, despite focal pathology.
Conclusions:
- Rabbits are highly sensitive to phospholamban level alterations, unlike mice, suggesting species-specific regulation of cardiac calcium handling.
- Exceeding a narrow phospholamban expression threshold results in significant morbidity and mortality in rabbits.
- These findings highlight critical differences in phospholamban's role between rabbits and mice, impacting its therapeutic potential for heart failure.
