Prolonged repolarization and triggered activity induced by adenoviral expression of HERG N629D in cardiomyocytes derived from stem cells
The long QT syndrome, N629D HERG mutation, alters the pore selectivity signature sequence, GFGN to GFGD. Heterologous co-expression of N629D and the wildtype HERG resulted in a relative loss of the selectivity of K+ over Na+, but its physiologic relevance has not been assessed in cardiac myocytes. A...
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| Veröffentlicht in: | Cardiovascular research 2004-02, Vol.61 (2), p.268-277 |
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| creator | GUOQI TENG XIANG ZHAO CROSS, James C PIN LI LEES-MILLER, James P JIQING GUO DYCK, Jason R. B DUFF, Henry J |
| description | The long QT syndrome, N629D HERG mutation, alters the pore selectivity signature sequence, GFGN to GFGD. Heterologous co-expression of N629D and the wildtype HERG resulted in a relative loss of the selectivity of K+ over Na+, but its physiologic relevance has not been assessed in cardiac myocytes.
Accordingly, N629D was overexpressed, via adenoviral gene transfer, in cardiomyocytes derived from mouse stem cells. Three IKr phenotypes were observed: (1) the wildtype-like IKr showed inward rectification and a positive tail current; (2) the N629D-like IKr showed outward rectification and an inward tail current; and (3) intermediate IKr showed a small outward tail current. Action potentials (AP) were paired with the IKr measurements in each cell. Resting membrane potential (RMP) was critically dependent on the IKr phenotype. The resting membrane potential of the cells was -61 +/- 5 mV (n=40) in wildtype, -63 +/- 3 mV (n=18) in wildtype-like IKr phenotype, -30 +/- 2 mV (n=12) in N629D-like and -47 +/- 2 mV (n=24) in intermediate phenotype (p |
| doi_str_mv | 10.1016/j.cardiores.2003.11.016 |
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Accordingly, N629D was overexpressed, via adenoviral gene transfer, in cardiomyocytes derived from mouse stem cells. Three IKr phenotypes were observed: (1) the wildtype-like IKr showed inward rectification and a positive tail current; (2) the N629D-like IKr showed outward rectification and an inward tail current; and (3) intermediate IKr showed a small outward tail current. Action potentials (AP) were paired with the IKr measurements in each cell. Resting membrane potential (RMP) was critically dependent on the IKr phenotype. The resting membrane potential of the cells was -61 +/- 5 mV (n=40) in wildtype, -63 +/- 3 mV (n=18) in wildtype-like IKr phenotype, -30 +/- 2 mV (n=12) in N629D-like and -47 +/- 2 mV (n=24) in intermediate phenotype (p<0.00001). Triggered action potential durations (APD) were: 62 +/- 12 ms (n=6) in wildtype, 65 +/- 11 ms (n=6) in wildtype-like IKr phenotypes and 106 +/- 10 ms (n=6) (p<0.01) in intermediate IKr phenotypes. Lowering [K+]o hyperpolarized wildtype cells and cells with a wildtype-like IKr phenotype, but depolarized those with intermediate phenotype (from -45 +/- 1 to -35 +/- 0.5 mV (n=12), p<0.01). In 6 of 12 cells, with intermediate phenotype, the hypokalemia-induced depolarization resulted in triggered activity. TTX suppressed this triggered activity.
Overexpression of N629D in cardiomyocytes derived from stem cells results in phenotypic variability in IKr, which was the critical determinant of the resting membrane potential, action potential duration and arrhythmogenic response to low [K+]o.</description><identifier>ISSN: 0008-6363</identifier><identifier>EISSN: 1755-3245</identifier><identifier>DOI: 10.1016/j.cardiores.2003.11.016</identifier><identifier>PMID: 14736543</identifier><identifier>CODEN: CVREAU</identifier><language>eng</language><publisher>Oxford: Oxford University Press</publisher><subject>Action Potentials ; Adenoviridae - genetics ; Animals ; Biological and medical sciences ; Cardiac dysrhythmias ; Cardiology. Vascular system ; Cation Transport Proteins - genetics ; Cell Differentiation ; Cells, Cultured ; Ether-A-Go-Go Potassium Channels ; Genetic Vectors - pharmacology ; Green Fluorescent Proteins ; Heart ; Long QT Syndrome - metabolism ; Luminescent Proteins - genetics ; Medical sciences ; Membrane Potentials ; Mice ; Myocytes, Cardiac - metabolism ; Patch-Clamp Techniques ; Point Mutation ; Potassium Channels - genetics ; Potassium Channels - metabolism ; Potassium Channels, Voltage-Gated ; Stem Cells - cytology ; Transduction, Genetic - methods</subject><ispartof>Cardiovascular research, 2004-02, Vol.61 (2), p.268-277</ispartof><rights>2004 INIST-CNRS</rights><lds50>peer_reviewed</lds50><oa>free_for_read</oa><woscitedreferencessubscribed>false</woscitedreferencessubscribed><citedby>FETCH-LOGICAL-c388t-3e455611d1a0182210cec856fbbb5a0ea69e46c1571fbf41ac80ae43695235f73</citedby></display><links><openurl>$$Topenurl_article</openurl><openurlfulltext>$$Topenurlfull_article</openurlfulltext><thumbnail>$$Tsyndetics_thumb_exl</thumbnail><link.rule.ids>314,780,784,27924,27925</link.rule.ids><backlink>$$Uhttp://pascal-francis.inist.fr/vibad/index.php?action=getRecordDetail&idt=15423801$$DView record in Pascal Francis$$Hfree_for_read</backlink><backlink>$$Uhttps://www.ncbi.nlm.nih.gov/pubmed/14736543$$D View this record in MEDLINE/PubMed$$Hfree_for_read</backlink></links><search><creatorcontrib>GUOQI TENG</creatorcontrib><creatorcontrib>XIANG ZHAO</creatorcontrib><creatorcontrib>CROSS, James C</creatorcontrib><creatorcontrib>PIN LI</creatorcontrib><creatorcontrib>LEES-MILLER, James P</creatorcontrib><creatorcontrib>JIQING GUO</creatorcontrib><creatorcontrib>DYCK, Jason R. B</creatorcontrib><creatorcontrib>DUFF, Henry J</creatorcontrib><title>Prolonged repolarization and triggered activity induced by adenoviral expression of HERG N629D in cardiomyocytes derived from stem cells</title><title>Cardiovascular research</title><addtitle>Cardiovasc Res</addtitle><description>The long QT syndrome, N629D HERG mutation, alters the pore selectivity signature sequence, GFGN to GFGD. Heterologous co-expression of N629D and the wildtype HERG resulted in a relative loss of the selectivity of K+ over Na+, but its physiologic relevance has not been assessed in cardiac myocytes.
Accordingly, N629D was overexpressed, via adenoviral gene transfer, in cardiomyocytes derived from mouse stem cells. Three IKr phenotypes were observed: (1) the wildtype-like IKr showed inward rectification and a positive tail current; (2) the N629D-like IKr showed outward rectification and an inward tail current; and (3) intermediate IKr showed a small outward tail current. Action potentials (AP) were paired with the IKr measurements in each cell. Resting membrane potential (RMP) was critically dependent on the IKr phenotype. The resting membrane potential of the cells was -61 +/- 5 mV (n=40) in wildtype, -63 +/- 3 mV (n=18) in wildtype-like IKr phenotype, -30 +/- 2 mV (n=12) in N629D-like and -47 +/- 2 mV (n=24) in intermediate phenotype (p<0.00001). Triggered action potential durations (APD) were: 62 +/- 12 ms (n=6) in wildtype, 65 +/- 11 ms (n=6) in wildtype-like IKr phenotypes and 106 +/- 10 ms (n=6) (p<0.01) in intermediate IKr phenotypes. Lowering [K+]o hyperpolarized wildtype cells and cells with a wildtype-like IKr phenotype, but depolarized those with intermediate phenotype (from -45 +/- 1 to -35 +/- 0.5 mV (n=12), p<0.01). In 6 of 12 cells, with intermediate phenotype, the hypokalemia-induced depolarization resulted in triggered activity. TTX suppressed this triggered activity.
Overexpression of N629D in cardiomyocytes derived from stem cells results in phenotypic variability in IKr, which was the critical determinant of the resting membrane potential, action potential duration and arrhythmogenic response to low [K+]o.</description><subject>Action Potentials</subject><subject>Adenoviridae - genetics</subject><subject>Animals</subject><subject>Biological and medical sciences</subject><subject>Cardiac dysrhythmias</subject><subject>Cardiology. Vascular system</subject><subject>Cation Transport Proteins - genetics</subject><subject>Cell Differentiation</subject><subject>Cells, Cultured</subject><subject>Ether-A-Go-Go Potassium Channels</subject><subject>Genetic Vectors - pharmacology</subject><subject>Green Fluorescent Proteins</subject><subject>Heart</subject><subject>Long QT Syndrome - metabolism</subject><subject>Luminescent Proteins - genetics</subject><subject>Medical sciences</subject><subject>Membrane Potentials</subject><subject>Mice</subject><subject>Myocytes, Cardiac - metabolism</subject><subject>Patch-Clamp Techniques</subject><subject>Point Mutation</subject><subject>Potassium Channels - genetics</subject><subject>Potassium Channels - metabolism</subject><subject>Potassium Channels, Voltage-Gated</subject><subject>Stem Cells - cytology</subject><subject>Transduction, Genetic - methods</subject><issn>0008-6363</issn><issn>1755-3245</issn><fulltext>true</fulltext><rsrctype>article</rsrctype><creationdate>2004</creationdate><recordtype>article</recordtype><sourceid>EIF</sourceid><recordid>eNpFkUFv1DAQhS0EokvhL4AvcEvwxLGTPaJSWqSKVhWcrYkzXnmVxIudXRF-QX82Xu2Kniw_f2_myY-xDyBKEKA_b0uLsfchUiorIWQJUGb9BVtBo1Qhq1q9ZCshRFtoqeUFe5PSNl-VaurX7ALqRmpVyxV7eohhCNOGeh5pFwaM_i_OPkwcp57P0W82FPMj2tkf_LxwP_V7m4Vu4djTFA4-4sDpzy5HSUdfcPz2-vGG_9DV-mvG-SnpuAS7zJR4T9Ef8gAXw8jTTCO3NAzpLXvlcEj07nxesl_frn9e3RZ39zffr77cFVa27VxIqpXSAD2ggLaqQFiyrdKu6zqFglCvqdYWVAOuczWgbQVSLfVaVVK5Rl6yT6e5uxh-7ynNZvTpmAAnCvtkWgEAeq0z2JxAG0NKkZzZRT9iXAwIcyzBbM3_EsyxBANgsp6d788r9t1I_bPv_OsZ-HgGMFkcXMTJ-vTMqbqSOYf8Bx93lVA</recordid><startdate>20040201</startdate><enddate>20040201</enddate><creator>GUOQI TENG</creator><creator>XIANG ZHAO</creator><creator>CROSS, James C</creator><creator>PIN LI</creator><creator>LEES-MILLER, James P</creator><creator>JIQING GUO</creator><creator>DYCK, Jason R. B</creator><creator>DUFF, Henry J</creator><general>Oxford University Press</general><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>7X8</scope></search><sort><creationdate>20040201</creationdate><title>Prolonged repolarization and triggered activity induced by adenoviral expression of HERG N629D in cardiomyocytes derived from stem cells</title><author>GUOQI TENG ; XIANG ZHAO ; CROSS, James C ; PIN LI ; LEES-MILLER, James P ; JIQING GUO ; DYCK, Jason R. B ; DUFF, Henry J</author></sort><facets><frbrtype>5</frbrtype><frbrgroupid>cdi_FETCH-LOGICAL-c388t-3e455611d1a0182210cec856fbbb5a0ea69e46c1571fbf41ac80ae43695235f73</frbrgroupid><rsrctype>articles</rsrctype><prefilter>articles</prefilter><language>eng</language><creationdate>2004</creationdate><topic>Action Potentials</topic><topic>Adenoviridae - genetics</topic><topic>Animals</topic><topic>Biological and medical sciences</topic><topic>Cardiac dysrhythmias</topic><topic>Cardiology. Vascular system</topic><topic>Cation Transport Proteins - genetics</topic><topic>Cell Differentiation</topic><topic>Cells, Cultured</topic><topic>Ether-A-Go-Go Potassium Channels</topic><topic>Genetic Vectors - pharmacology</topic><topic>Green Fluorescent Proteins</topic><topic>Heart</topic><topic>Long QT Syndrome - metabolism</topic><topic>Luminescent Proteins - genetics</topic><topic>Medical sciences</topic><topic>Membrane Potentials</topic><topic>Mice</topic><topic>Myocytes, Cardiac - metabolism</topic><topic>Patch-Clamp Techniques</topic><topic>Point Mutation</topic><topic>Potassium Channels - genetics</topic><topic>Potassium Channels - metabolism</topic><topic>Potassium Channels, Voltage-Gated</topic><topic>Stem Cells - cytology</topic><topic>Transduction, Genetic - methods</topic><toplevel>peer_reviewed</toplevel><toplevel>online_resources</toplevel><creatorcontrib>GUOQI TENG</creatorcontrib><creatorcontrib>XIANG ZHAO</creatorcontrib><creatorcontrib>CROSS, James C</creatorcontrib><creatorcontrib>PIN LI</creatorcontrib><creatorcontrib>LEES-MILLER, James P</creatorcontrib><creatorcontrib>JIQING GUO</creatorcontrib><creatorcontrib>DYCK, Jason R. B</creatorcontrib><creatorcontrib>DUFF, Henry J</creatorcontrib><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>MEDLINE - Academic</collection><jtitle>Cardiovascular research</jtitle></facets><delivery><delcategory>Remote Search Resource</delcategory><fulltext>fulltext</fulltext></delivery><addata><au>GUOQI TENG</au><au>XIANG ZHAO</au><au>CROSS, James C</au><au>PIN LI</au><au>LEES-MILLER, James P</au><au>JIQING GUO</au><au>DYCK, Jason R. B</au><au>DUFF, Henry J</au><format>journal</format><genre>article</genre><ristype>JOUR</ristype><atitle>Prolonged repolarization and triggered activity induced by adenoviral expression of HERG N629D in cardiomyocytes derived from stem cells</atitle><jtitle>Cardiovascular research</jtitle><addtitle>Cardiovasc Res</addtitle><date>2004-02-01</date><risdate>2004</risdate><volume>61</volume><issue>2</issue><spage>268</spage><epage>277</epage><pages>268-277</pages><issn>0008-6363</issn><eissn>1755-3245</eissn><coden>CVREAU</coden><abstract>The long QT syndrome, N629D HERG mutation, alters the pore selectivity signature sequence, GFGN to GFGD. Heterologous co-expression of N629D and the wildtype HERG resulted in a relative loss of the selectivity of K+ over Na+, but its physiologic relevance has not been assessed in cardiac myocytes.
Accordingly, N629D was overexpressed, via adenoviral gene transfer, in cardiomyocytes derived from mouse stem cells. Three IKr phenotypes were observed: (1) the wildtype-like IKr showed inward rectification and a positive tail current; (2) the N629D-like IKr showed outward rectification and an inward tail current; and (3) intermediate IKr showed a small outward tail current. Action potentials (AP) were paired with the IKr measurements in each cell. Resting membrane potential (RMP) was critically dependent on the IKr phenotype. The resting membrane potential of the cells was -61 +/- 5 mV (n=40) in wildtype, -63 +/- 3 mV (n=18) in wildtype-like IKr phenotype, -30 +/- 2 mV (n=12) in N629D-like and -47 +/- 2 mV (n=24) in intermediate phenotype (p<0.00001). Triggered action potential durations (APD) were: 62 +/- 12 ms (n=6) in wildtype, 65 +/- 11 ms (n=6) in wildtype-like IKr phenotypes and 106 +/- 10 ms (n=6) (p<0.01) in intermediate IKr phenotypes. Lowering [K+]o hyperpolarized wildtype cells and cells with a wildtype-like IKr phenotype, but depolarized those with intermediate phenotype (from -45 +/- 1 to -35 +/- 0.5 mV (n=12), p<0.01). In 6 of 12 cells, with intermediate phenotype, the hypokalemia-induced depolarization resulted in triggered activity. TTX suppressed this triggered activity.
Overexpression of N629D in cardiomyocytes derived from stem cells results in phenotypic variability in IKr, which was the critical determinant of the resting membrane potential, action potential duration and arrhythmogenic response to low [K+]o.</abstract><cop>Oxford</cop><pub>Oxford University Press</pub><pmid>14736543</pmid><doi>10.1016/j.cardiores.2003.11.016</doi><tpages>10</tpages><oa>free_for_read</oa></addata></record> |
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| subjects | Action Potentials Adenoviridae - genetics Animals Biological and medical sciences Cardiac dysrhythmias Cardiology. Vascular system Cation Transport Proteins - genetics Cell Differentiation Cells, Cultured Ether-A-Go-Go Potassium Channels Genetic Vectors - pharmacology Green Fluorescent Proteins Heart Long QT Syndrome - metabolism Luminescent Proteins - genetics Medical sciences Membrane Potentials Mice Myocytes, Cardiac - metabolism Patch-Clamp Techniques Point Mutation Potassium Channels - genetics Potassium Channels - metabolism Potassium Channels, Voltage-Gated Stem Cells - cytology Transduction, Genetic - methods |
| title | Prolonged repolarization and triggered activity induced by adenoviral expression of HERG N629D in cardiomyocytes derived from stem cells |
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