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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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. |
doi_str_mv | 10.1007/s11248-007-9139-2 |
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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&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. 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><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. Psychology</subject><subject>Gene Expression - genetics</subject><subject>Genetic Engineering</subject><subject>Genetic technics</subject><subject>Heart - physiology</subject><subject>Heart failure</subject><subject>Immunoenzyme Techniques</subject><subject>Life Sciences</subject><subject>Male</subject><subject>Methods. Procedures. Technologies</subject><subject>Microscopy, Electron, Transmission</subject><subject>Molecular Medicine</subject><subject>Molecular Sequence Data</subject><subject>Original Paper</subject><subject>Phospholamban</subject><subject>Plant Genetics and Genomics</subject><subject>Rabbits</subject><subject>Receptors, Adrenergic, beta - metabolism</subject><subject>Reverse Transcriptase Polymerase Chain Reaction</subject><subject>RNA, Messenger - genetics</subject><subject>RNA, Messenger - metabolism</subject><subject>Sarcoplasmic Reticulum - metabolism</subject><subject>Transgenic animals and transgenic plants</subject><subject>Transgenic rabbits</subject><subject>Transgenics</subject><issn>0962-8819</issn><issn>1573-9368</issn><fulltext>true</fulltext><rsrctype>article</rsrctype><creationdate>2008</creationdate><recordtype>article</recordtype><sourceid>EIF</sourceid><sourceid>ABUWG</sourceid><sourceid>AFKRA</sourceid><sourceid>AZQEC</sourceid><sourceid>BENPR</sourceid><sourceid>CCPQU</sourceid><sourceid>DWQXO</sourceid><sourceid>GNUQQ</sourceid><recordid>eNqFkk9vEzEQxS1ERUPhA3CBCKncFuzxrv9cKqGqQKVKIEHPltfxJq42dvAkVfvtmWijFjjAybbmN8_P88zYK8HfC871BxQCWtPQtrFC2gaesJnotGysVOYpm3GroDFG2GP2HPGGc-oy8hk7FtoY6CSfMfi2KrhZldGve5_n5TbWeLepETGVPE95vq0-4zLmFObV933a4gt2NPgR48vDesKuP138OP_SXH39fHn-8aoJSphtI7VpjY0LOqmBKwDRdz4sYlSLaIKMg_Sqh0VH7oOOAKA6JdtgeuEtVyrIE3Y26W52_Zp0YiYvo9vUtPb13hWf3J-VnFZuWW4dSKW4NCTw7iBQy89dxK1bJwxxHH2OZYdO81YIzeG_IHDb0ig7At_-Bd6UXc00BQcgueHQaoLEBIVaEGscHiwL7va5uSk3t9_uc3N7B69_f-tjxyEoAk4PgMfgx4FSCQkfOOBEylYQBxOHVMrLWB8d_uv2N1PT4Ivzy0rC199JUtJ30Z0l6heuPrkJ</recordid><startdate>20080401</startdate><enddate>20080401</enddate><creator>Pattison, James Scott</creator><creator>Waggoner, Jason R</creator><creator>James, Jeanne</creator><creator>Martin, Lisa</creator><creator>Gulick, James</creator><creator>Osinska, Hanna</creator><creator>Klevitsky, Raisa</creator><creator>Kranias, Evangelia G</creator><creator>Robbins, Jeffrey</creator><general>Dordrecht : Springer Netherlands</general><general>Springer Netherlands</general><general>Springer</general><general>Springer Nature B.V</general><scope>FBQ</scope><scope>IQODW</scope><scope>CGR</scope><scope>CUY</scope><scope>CVF</scope><scope>ECM</scope><scope>EIF</scope><scope>NPM</scope><scope>AAYXX</scope><scope>CITATION</scope><scope>3V.</scope><scope>7TK</scope><scope>7TM</scope><scope>7X7</scope><scope>7XB</scope><scope>88A</scope><scope>88E</scope><scope>8AO</scope><scope>8FD</scope><scope>8FE</scope><scope>8FH</scope><scope>8FI</scope><scope>8FJ</scope><scope>8FK</scope><scope>ABUWG</scope><scope>AFKRA</scope><scope>AZQEC</scope><scope>BBNVY</scope><scope>BENPR</scope><scope>BHPHI</scope><scope>CCPQU</scope><scope>DWQXO</scope><scope>FR3</scope><scope>FYUFA</scope><scope>GHDGH</scope><scope>GNUQQ</scope><scope>HCIFZ</scope><scope>K9.</scope><scope>LK8</scope><scope>M0S</scope><scope>M1P</scope><scope>M7P</scope><scope>P64</scope><scope>PQEST</scope><scope>PQQKQ</scope><scope>PQUKI</scope><scope>PRINS</scope><scope>RC3</scope><scope>7QO</scope><scope>7X8</scope><scope>5PM</scope></search><sort><creationdate>20080401</creationdate><title>Phospholamban overexpression in transgenic rabbits</title><author>Pattison, James Scott ; Waggoner, Jason R ; James, Jeanne ; Martin, Lisa ; Gulick, James ; Osinska, Hanna ; Klevitsky, Raisa ; Kranias, Evangelia G ; Robbins, Jeffrey</author></sort><facets><frbrtype>5</frbrtype><frbrgroupid>cdi_FETCH-LOGICAL-c618t-378489edc616f06221b5acdee6de8c3ef3a6b2d5007c7e22265634c8b1a9066c3</frbrgroupid><rsrctype>articles</rsrctype><prefilter>articles</prefilter><language>eng</language><creationdate>2008</creationdate><topic>Amino Acid Sequence</topic><topic>Animal Genetics and Genomics</topic><topic>Animals</topic><topic>Animals, Genetically Modified</topic><topic>Biological and medical sciences</topic><topic>Biomedical and Life Sciences</topic><topic>Biomedical Engineering/Biotechnology</topic><topic>Biotechnology</topic><topic>calcium</topic><topic>Calcium - metabolism</topic><topic>Calcium-Binding Proteins - physiology</topic><topic>Cells, Cultured</topic><topic>DNA Primers</topic><topic>Echocardiography</topic><topic>Female</topic><topic>Fundamental and applied biological sciences. Psychology</topic><topic>Gene Expression - genetics</topic><topic>Genetic Engineering</topic><topic>Genetic technics</topic><topic>Heart - physiology</topic><topic>Heart failure</topic><topic>Immunoenzyme Techniques</topic><topic>Life Sciences</topic><topic>Male</topic><topic>Methods. Procedures. Technologies</topic><topic>Microscopy, Electron, Transmission</topic><topic>Molecular Medicine</topic><topic>Molecular Sequence Data</topic><topic>Original Paper</topic><topic>Phospholamban</topic><topic>Plant Genetics and Genomics</topic><topic>Rabbits</topic><topic>Receptors, Adrenergic, beta - metabolism</topic><topic>Reverse Transcriptase Polymerase Chain Reaction</topic><topic>RNA, Messenger - genetics</topic><topic>RNA, Messenger - metabolism</topic><topic>Sarcoplasmic Reticulum - metabolism</topic><topic>Transgenic animals and transgenic plants</topic><topic>Transgenic rabbits</topic><topic>Transgenics</topic><toplevel>peer_reviewed</toplevel><toplevel>online_resources</toplevel><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><collection>AGRIS</collection><collection>Pascal-Francis</collection><collection>Medline</collection><collection>MEDLINE</collection><collection>MEDLINE (Ovid)</collection><collection>MEDLINE</collection><collection>MEDLINE</collection><collection>PubMed</collection><collection>CrossRef</collection><collection>ProQuest Central (Corporate)</collection><collection>Neurosciences Abstracts</collection><collection>Nucleic Acids Abstracts</collection><collection>Health & Medical Collection</collection><collection>ProQuest Central (purchase pre-March 2016)</collection><collection>Biology Database (Alumni Edition)</collection><collection>Medical Database (Alumni Edition)</collection><collection>ProQuest Pharma Collection</collection><collection>Technology Research Database</collection><collection>ProQuest SciTech Collection</collection><collection>ProQuest Natural Science Collection</collection><collection>Hospital Premium Collection</collection><collection>Hospital Premium Collection (Alumni Edition)</collection><collection>ProQuest Central (Alumni) (purchase pre-March 2016)</collection><collection>ProQuest Central (Alumni Edition)</collection><collection>ProQuest Central UK/Ireland</collection><collection>ProQuest Central Essentials</collection><collection>Biological Science Collection</collection><collection>ProQuest Central</collection><collection>Natural Science Collection (ProQuest)</collection><collection>ProQuest One Community College</collection><collection>ProQuest Central Korea</collection><collection>Engineering Research Database</collection><collection>Health Research Premium Collection</collection><collection>Health Research Premium Collection (Alumni)</collection><collection>ProQuest Central Student</collection><collection>SciTech Premium Collection</collection><collection>ProQuest Health & Medical Complete (Alumni)</collection><collection>ProQuest Biological Science Collection</collection><collection>Health & Medical Collection (Alumni Edition)</collection><collection>Medical Database</collection><collection>Biological Science Database</collection><collection>Biotechnology and BioEngineering Abstracts</collection><collection>ProQuest One Academic Eastern Edition (DO NOT USE)</collection><collection>ProQuest One Academic</collection><collection>ProQuest One Academic UKI Edition</collection><collection>ProQuest Central China</collection><collection>Genetics Abstracts</collection><collection>Biotechnology Research Abstracts</collection><collection>MEDLINE - Academic</collection><collection>PubMed Central (Full Participant titles)</collection><jtitle>Transgenic research</jtitle></facets><delivery><delcategory>Remote Search Resource</delcategory><fulltext>fulltext</fulltext></delivery><addata><au>Pattison, James Scott</au><au>Waggoner, Jason R</au><au>James, Jeanne</au><au>Martin, Lisa</au><au>Gulick, James</au><au>Osinska, Hanna</au><au>Klevitsky, Raisa</au><au>Kranias, Evangelia G</au><au>Robbins, Jeffrey</au><format>journal</format><genre>article</genre><ristype>JOUR</ristype><atitle>Phospholamban overexpression in transgenic rabbits</atitle><jtitle>Transgenic research</jtitle><stitle>Transgenic Res</stitle><addtitle>Transgenic Res</addtitle><date>2008-04-01</date><risdate>2008</risdate><volume>17</volume><issue>2</issue><spage>157</spage><epage>170</epage><pages>157-170</pages><issn>0962-8819</issn><eissn>1573-9368</eissn><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.</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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