Phospholamban overexpression in transgenic rabbits

James Scott Pattison, Jason R. Waggoner, Jeanne James, Lisa Martin, James Gulick, Hanna Osinska, Raisa Klevitsky, Evangelia G. Kranias, Jeffrey Robbins

Research output: Contribution to journalArticle

22 Scopus citations

Abstract

There has been considerable interest in pursuing phospholamban as a putative therapeutic target for overcoming depressed calcium handling in human heart failure. Studies predominantly done in mice have shown that phospholamban is a key regulator of sarcoplasmic reticulum calcium cycling and cardiac function. However, mice differ significantly from humans in how they regulate calcium, whereas rabbits better recapitulate human cardiac function and calcium handling. To investigate phospholamban's role in the rabbit heart, transgenic rabbits that overexpressed wild-type phospholamban in the ventricular cardiomyocytes and slow-twitch skeletal muscles were generated. Rabbits expressing high levels of phospholamban were not viable due to severe skeletal muscle wasting, the onset of cardiac pathology and early death. A viable transgenic line exhibited a 30% increase in PLN protein levels in the heart. These animals showed isolated foci of cardiac pathology, but cardiac function as well as the response to β-adrenergic stimulation were normal. SR-calcium uptake measurements showed that the transgenic hearts had the expected reduced affinity for calcium. The data show that phospholamban-overexpressing transgenic rabbits differ markedly in phenotype from analogous transgenic mice in that rabbits are quite sensitive to alterations in phospholamban levels. Exceeding a relatively narrow window of phospholamban expression results in significant morbidity and early death.

Original languageEnglish (US)
Pages (from-to)157-170
Number of pages14
JournalTransgenic Research
Volume17
Issue number2
DOIs
StatePublished - Apr 2008

Keywords

  • Calcium
  • Heart failure
  • Phospholamban
  • Transgenic rabbits

ASJC Scopus subject areas

  • Biotechnology
  • Animal Science and Zoology
  • Agronomy and Crop Science
  • Genetics

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  • Cite this

    Pattison, J. S., Waggoner, J. R., James, J., Martin, L., Gulick, J., Osinska, H., Klevitsky, R., Kranias, E. G., & Robbins, J. (2008). Phospholamban overexpression in transgenic rabbits. Transgenic Research, 17(2), 157-170. https://doi.org/10.1007/s11248-007-9139-2