Faculty Collaboration Database

Phospholamban overexpression in transgenic rabbits. Transgenic Res 2008 Apr;17(2):157-70

Date

09/21/2007

Pubmed ID

17882530

Pubmed Central ID

PMC2366038

DOI

10.1007/s11248-007-9139-2

Scopus ID

2-s2.0-41049089262 (requires institutional sign-in at Scopus site)   24 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 beta-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.

Author List

Pattison JS, Waggoner JR, James J, Martin L, Gulick J, Osinska H, Klevitsky R, Kranias EG, Robbins J

MESH terms used to index this publication - Major topics in bold

Amino Acid Sequence
Animals
Animals, Genetically Modified
Calcium
Calcium-Binding Proteins
Cells, Cultured
DNA Primers
Echocardiography
Female
Gene Expression
Heart
Immunoenzyme Techniques
Male
Microscopy, Electron, Transmission
Molecular Sequence Data
RNA, Messenger
Rabbits
Receptors, Adrenergic, beta
Reverse Transcriptase Polymerase Chain Reaction
Sarcoplasmic Reticulum