Phospholamban overexpression in transgenic rabbits

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...

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Veröffentlicht in:Transgenic research 2008-04, Vol.17 (2), p.157-170
Hauptverfasser: Pattison, James Scott, Waggoner, Jason R, James, Jeanne, Martin, Lisa, Gulick, James, Osinska, Hanna, Klevitsky, Raisa, Kranias, Evangelia G, Robbins, Jeffrey
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container_end_page 170
container_issue 2
container_start_page 157
container_title Transgenic research
container_volume 17
creator Pattison, James Scott
Waggoner, Jason R
James, Jeanne
Martin, Lisa
Gulick, James
Osinska, Hanna
Klevitsky, Raisa
Kranias, Evangelia G
Robbins, Jeffrey
description 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.
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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.</description><identifier>ISSN: 0962-8819</identifier><identifier>EISSN: 1573-9368</identifier><identifier>DOI: 10.1007/s11248-007-9139-2</identifier><identifier>PMID: 17882530</identifier><language>eng</language><publisher>Dordrecht: Dordrecht : Springer Netherlands</publisher><subject>Amino Acid Sequence ; Animal Genetics and Genomics ; Animals ; Animals, Genetically Modified ; Biological and medical sciences ; Biomedical and Life Sciences ; Biomedical Engineering/Biotechnology ; Biotechnology ; calcium ; Calcium - metabolism ; Calcium-Binding Proteins - physiology ; Cells, Cultured ; DNA Primers ; Echocardiography ; Female ; Fundamental and applied biological sciences. Psychology ; Gene Expression - genetics ; Genetic Engineering ; Genetic technics ; Heart - physiology ; Heart failure ; Immunoenzyme Techniques ; Life Sciences ; Male ; Methods. Procedures. Technologies ; Microscopy, Electron, Transmission ; Molecular Medicine ; Molecular Sequence Data ; Original Paper ; Phospholamban ; Plant Genetics and Genomics ; Rabbits ; Receptors, Adrenergic, beta - metabolism ; Reverse Transcriptase Polymerase Chain Reaction ; RNA, Messenger - genetics ; RNA, Messenger - metabolism ; Sarcoplasmic Reticulum - metabolism ; Transgenic animals and transgenic plants ; Transgenic rabbits ; Transgenics</subject><ispartof>Transgenic research, 2008-04, Vol.17 (2), p.157-170</ispartof><rights>Springer Science+Business Media B.V. 2007</rights><rights>2008 INIST-CNRS</rights><rights>Springer Science+Business Media B.V. 2008</rights><lds50>peer_reviewed</lds50><oa>free_for_read</oa><woscitedreferencessubscribed>false</woscitedreferencessubscribed><citedby>FETCH-LOGICAL-c618t-378489edc616f06221b5acdee6de8c3ef3a6b2d5007c7e22265634c8b1a9066c3</citedby><cites>FETCH-LOGICAL-c618t-378489edc616f06221b5acdee6de8c3ef3a6b2d5007c7e22265634c8b1a9066c3</cites></display><links><openurl>$$Topenurl_article</openurl><openurlfulltext>$$Topenurlfull_article</openurlfulltext><thumbnail>$$Tsyndetics_thumb_exl</thumbnail><linktopdf>$$Uhttps://link.springer.com/content/pdf/10.1007/s11248-007-9139-2$$EPDF$$P50$$Gspringer$$H</linktopdf><linktohtml>$$Uhttps://link.springer.com/10.1007/s11248-007-9139-2$$EHTML$$P50$$Gspringer$$H</linktohtml><link.rule.ids>230,314,780,784,885,27924,27925,41488,42557,51319</link.rule.ids><backlink>$$Uhttp://pascal-francis.inist.fr/vibad/index.php?action=getRecordDetail&amp;idt=20178341$$DView record in Pascal Francis$$Hfree_for_read</backlink><backlink>$$Uhttps://www.ncbi.nlm.nih.gov/pubmed/17882530$$D View this record in MEDLINE/PubMed$$Hfree_for_read</backlink></links><search><creatorcontrib>Pattison, James Scott</creatorcontrib><creatorcontrib>Waggoner, Jason R</creatorcontrib><creatorcontrib>James, Jeanne</creatorcontrib><creatorcontrib>Martin, Lisa</creatorcontrib><creatorcontrib>Gulick, James</creatorcontrib><creatorcontrib>Osinska, Hanna</creatorcontrib><creatorcontrib>Klevitsky, Raisa</creatorcontrib><creatorcontrib>Kranias, Evangelia G</creatorcontrib><creatorcontrib>Robbins, Jeffrey</creatorcontrib><title>Phospholamban overexpression in transgenic rabbits</title><title>Transgenic research</title><addtitle>Transgenic Res</addtitle><addtitle>Transgenic Res</addtitle><description>There has been considerable interest in pursuing phospholamban as a putative therapeutic target for overcoming depressed calcium handling in human heart failure. 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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.</description><subject>Amino Acid Sequence</subject><subject>Animal Genetics and Genomics</subject><subject>Animals</subject><subject>Animals, Genetically Modified</subject><subject>Biological and medical sciences</subject><subject>Biomedical and Life Sciences</subject><subject>Biomedical Engineering/Biotechnology</subject><subject>Biotechnology</subject><subject>calcium</subject><subject>Calcium - metabolism</subject><subject>Calcium-Binding Proteins - physiology</subject><subject>Cells, Cultured</subject><subject>DNA Primers</subject><subject>Echocardiography</subject><subject>Female</subject><subject>Fundamental and applied biological sciences. 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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.</abstract><cop>Dordrecht</cop><pub>Dordrecht : Springer Netherlands</pub><pmid>17882530</pmid><doi>10.1007/s11248-007-9139-2</doi><tpages>14</tpages><oa>free_for_read</oa></addata></record>
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subjects Amino Acid Sequence
Animal Genetics and Genomics
Animals
Animals, Genetically Modified
Biological and medical sciences
Biomedical and Life Sciences
Biomedical Engineering/Biotechnology
Biotechnology
calcium
Calcium - metabolism
Calcium-Binding Proteins - physiology
Cells, Cultured
DNA Primers
Echocardiography
Female
Fundamental and applied biological sciences. Psychology
Gene Expression - genetics
Genetic Engineering
Genetic technics
Heart - physiology
Heart failure
Immunoenzyme Techniques
Life Sciences
Male
Methods. Procedures. Technologies
Microscopy, Electron, Transmission
Molecular Medicine
Molecular Sequence Data
Original Paper
Phospholamban
Plant Genetics and Genomics
Rabbits
Receptors, Adrenergic, beta - metabolism
Reverse Transcriptase Polymerase Chain Reaction
RNA, Messenger - genetics
RNA, Messenger - metabolism
Sarcoplasmic Reticulum - metabolism
Transgenic animals and transgenic plants
Transgenic rabbits
Transgenics
title Phospholamban overexpression in transgenic rabbits
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