title: Phospholamban overexpression in transgenic rabbits.
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.
authors: Division of Molecular Cardiovascular Biology, Cincinnati Children's Hospital Research Foundation, 3333 Burnet Avenue, Cincinnati, OH 45229-3039, USA.
authors: James Scott
authors: JS
authors: Pattison
authors: Jason R
authors: JR
authors: Waggoner
authors: Jeanne
authors: J
authors: James
authors: Lisa
authors: L
authors: Martin
authors: James
authors: J
authors: Gulick
authors: Hanna
authors: H
authors: Osinska
authors: Raisa
authors: R
authors: Klevitsky
authors: Evangelia G
authors: EG
authors: Kranias
authors: Jeffrey
authors: J
authors: Robbins
mesh_terms: D000595:Amino Acid Sequence; D000818:Animals; D030801:Animals, Genetically Modified; D002118:Calcium / Q000378:metabolism*; D002135:Calcium-Binding Proteins / Q000502:physiology*; D002478:Cells, Cultured; D017931:DNA Primers; D004452:Echocardiography; D005260:Female; D015870:Gene Expression / Q000235:genetics*; D006321:Heart / Q000502:physiology*; D007124:Immunoenzyme Techniques; D008297:Male; D046529:Microscopy, Electron, Transmission; D008969:Molecular Sequence Data; D012333:RNA, Messenger / Q000235:genetics / Q000378:metabolism; D011817:Rabbits; D011943:Receptors, Adrenergic, beta / Q000378:metabolism; D020133:Reverse Transcriptase Polymerase Chain Reaction; D012519:Sarcoplasmic Reticulum / Q000378:metabolism; D000099211:Phospholamban
chemical_list: D002118:Calcium; D002135:Calcium-Binding Proteins; D017931:DNA Primers; D012333:RNA, Messenger; D011943:Receptors, Adrenergic, beta; D000099211:Phospholamban