Murine cardiac mtDNA: effects of transgenic manipulation of nucleoside phosphorylation
Mitochondrial toxicity results from pyrimidine nucleoside reverse transcriptase inhibitors (NRTIs) for HIV/AIDS. In the heart, this can deplete mitochondrial (mt) DNA and cause cardiac dysfunction (eg, left ventricle hypertrophy, LVH). Four unique transgenic, cardiac-targeted overexpressors (TGs) we...
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| Veröffentlicht in: | Laboratory investigation 2009-02, Vol.89 (2), p.122-130 |
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| creator | Kohler, James J Hosseini, Seyed H Cucoranu, Ioan Hoying-Brandt, Amy Green, Elgin Johnson, David Wittich, Bree Srivastava, Jaya Ivey, Kristopher Fields, Earl Russ, Rodney Raper, C Michael Santoianni, Robert Lewis, William |
| description | Mitochondrial toxicity results from pyrimidine nucleoside reverse transcriptase inhibitors (NRTIs) for HIV/AIDS. In the heart, this can deplete mitochondrial (mt) DNA and cause cardiac dysfunction (eg, left ventricle hypertrophy, LVH). Four unique transgenic, cardiac-targeted overexpressors (TGs) were generated to determine their individual impact on native mitochondrial biogenesis and effects of NRTI administration on development of mitochondrial toxicity. TGs included cardiac-specific overexpression of native thymidine kinase 2 (TK2), two pathogenic TK2 mutants (H121N and I212N), and a mutant of mtDNA polymerase, pol-
γ
(Y955C). Each was treated with antiretrovirals (AZT-HAART, 3 or 10 weeks, zidovudine (AZT) + lamivudine (3TC) + indinavir, or vehicle control). Parameters included left ventricle (LV) performance (echocardiography), LV mtDNA abundance (real-time PCR), and mitochondrial fine structure (electron microscopy, EM) as a function of duration of treatment and presence of TG. mtDNA abundance significantly decreased in Y955C TG, increased in TK2 native and I212N TGs, and was unchanged in H121N TGs at 10 weeks regardless of treatment. Y955C and I212N TGs exhibited LVH during growth irrespective of treatment. Y955C TGs exhibited cardiomyopathy (CM) at 3 and 10 weeks irrespective of treatment, whereas H121N and I212N TGs exhibited CM only after 10 weeks AZT-HAART. EM features were consistent with cardiac dysfunction. mtDNA abundance and cardiac functional changes were related to TG expression of mitochondrially related genes, mutations thereof, and NRTIs. |
| doi_str_mv | 10.1038/labinvest.2008.121 |
| format | Article |
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γ
(Y955C). Each was treated with antiretrovirals (AZT-HAART, 3 or 10 weeks, zidovudine (AZT) + lamivudine (3TC) + indinavir, or vehicle control). Parameters included left ventricle (LV) performance (echocardiography), LV mtDNA abundance (real-time PCR), and mitochondrial fine structure (electron microscopy, EM) as a function of duration of treatment and presence of TG. mtDNA abundance significantly decreased in Y955C TG, increased in TK2 native and I212N TGs, and was unchanged in H121N TGs at 10 weeks regardless of treatment. Y955C and I212N TGs exhibited LVH during growth irrespective of treatment. Y955C TGs exhibited cardiomyopathy (CM) at 3 and 10 weeks irrespective of treatment, whereas H121N and I212N TGs exhibited CM only after 10 weeks AZT-HAART. EM features were consistent with cardiac dysfunction. mtDNA abundance and cardiac functional changes were related to TG expression of mitochondrially related genes, mutations thereof, and NRTIs.</description><identifier>ISSN: 0023-6837</identifier><identifier>EISSN: 1530-0307</identifier><identifier>DOI: 10.1038/labinvest.2008.121</identifier><identifier>PMID: 19079325</identifier><identifier>CODEN: LAINAW</identifier><language>eng</language><publisher>New York: Nature Publishing Group US</publisher><subject>Animals ; Anti-HIV Agents - toxicity ; Antiretroviral Therapy, Highly Active ; Biological and medical sciences ; Biotechnology ; Cardiomyopathy, Dilated - chemically induced ; Cardiomyopathy, Dilated - metabolism ; Cardiomyopathy, Dilated - pathology ; Cell Line ; DNA, Mitochondrial - analysis ; DNA, Mitochondrial - metabolism ; Echocardiography ; Female ; Fundamental and applied biological sciences. Psychology ; Heart Ventricles - chemistry ; Heart Ventricles - drug effects ; Heart Ventricles - metabolism ; Human immunodeficiency virus ; Hypertrophy, Left Ventricular - chemically induced ; Hypertrophy, Left Ventricular - diagnostic imaging ; Hypertrophy, Left Ventricular - metabolism ; Indinavir - toxicity ; Investigative techniques, diagnostic techniques (general aspects) ; Laboratory Medicine ; Lamivudine - toxicity ; Male ; Medical sciences ; Medicine ; Medicine & Public Health ; Mice ; Mice, Transgenic ; Mitochondria, Heart - drug effects ; Mitochondria, Heart - metabolism ; Mitochondria, Heart - ultrastructure ; Myocytes, Cardiac - drug effects ; Myocytes, Cardiac - metabolism ; Myocytes, Cardiac - ultrastructure ; Pathology ; Phosphorylation ; research-article ; Reverse Transcriptase Inhibitors - toxicity ; Thymidine Kinase - genetics ; Thymidine Kinase - metabolism ; Zidovudine - toxicity</subject><ispartof>Laboratory investigation, 2009-02, Vol.89 (2), p.122-130</ispartof><rights>United States and Canadian Academy of Pathology, Inc. 2009</rights><rights>2009 INIST-CNRS</rights><rights>Copyright Nature Publishing Group Feb 2009</rights><lds50>peer_reviewed</lds50><oa>free_for_read</oa><woscitedreferencessubscribed>false</woscitedreferencessubscribed><citedby>FETCH-LOGICAL-c533t-3643d48e73442289862d587c54ad848d87cfe20894808b36fe56a0901078b5a3</citedby><cites>FETCH-LOGICAL-c533t-3643d48e73442289862d587c54ad848d87cfe20894808b36fe56a0901078b5a3</cites></display><links><openurl>$$Topenurl_article</openurl><openurlfulltext>$$Topenurlfull_article</openurlfulltext><thumbnail>$$Tsyndetics_thumb_exl</thumbnail><link.rule.ids>230,314,776,780,881,27901,27902</link.rule.ids><backlink>$$Uhttp://pascal-francis.inist.fr/vibad/index.php?action=getRecordDetail&idt=21152029$$DView record in Pascal Francis$$Hfree_for_read</backlink><backlink>$$Uhttps://www.ncbi.nlm.nih.gov/pubmed/19079325$$D View this record in MEDLINE/PubMed$$Hfree_for_read</backlink></links><search><creatorcontrib>Kohler, James J</creatorcontrib><creatorcontrib>Hosseini, Seyed H</creatorcontrib><creatorcontrib>Cucoranu, Ioan</creatorcontrib><creatorcontrib>Hoying-Brandt, Amy</creatorcontrib><creatorcontrib>Green, Elgin</creatorcontrib><creatorcontrib>Johnson, David</creatorcontrib><creatorcontrib>Wittich, Bree</creatorcontrib><creatorcontrib>Srivastava, Jaya</creatorcontrib><creatorcontrib>Ivey, Kristopher</creatorcontrib><creatorcontrib>Fields, Earl</creatorcontrib><creatorcontrib>Russ, Rodney</creatorcontrib><creatorcontrib>Raper, C Michael</creatorcontrib><creatorcontrib>Santoianni, Robert</creatorcontrib><creatorcontrib>Lewis, William</creatorcontrib><title>Murine cardiac mtDNA: effects of transgenic manipulation of nucleoside phosphorylation</title><title>Laboratory investigation</title><addtitle>Lab Invest</addtitle><addtitle>Lab Invest</addtitle><description>Mitochondrial toxicity results from pyrimidine nucleoside reverse transcriptase inhibitors (NRTIs) for HIV/AIDS. In the heart, this can deplete mitochondrial (mt) DNA and cause cardiac dysfunction (eg, left ventricle hypertrophy, LVH). Four unique transgenic, cardiac-targeted overexpressors (TGs) were generated to determine their individual impact on native mitochondrial biogenesis and effects of NRTI administration on development of mitochondrial toxicity. TGs included cardiac-specific overexpression of native thymidine kinase 2 (TK2), two pathogenic TK2 mutants (H121N and I212N), and a mutant of mtDNA polymerase, pol-
γ
(Y955C). Each was treated with antiretrovirals (AZT-HAART, 3 or 10 weeks, zidovudine (AZT) + lamivudine (3TC) + indinavir, or vehicle control). Parameters included left ventricle (LV) performance (echocardiography), LV mtDNA abundance (real-time PCR), and mitochondrial fine structure (electron microscopy, EM) as a function of duration of treatment and presence of TG. mtDNA abundance significantly decreased in Y955C TG, increased in TK2 native and I212N TGs, and was unchanged in H121N TGs at 10 weeks regardless of treatment. Y955C and I212N TGs exhibited LVH during growth irrespective of treatment. Y955C TGs exhibited cardiomyopathy (CM) at 3 and 10 weeks irrespective of treatment, whereas H121N and I212N TGs exhibited CM only after 10 weeks AZT-HAART. EM features were consistent with cardiac dysfunction. mtDNA abundance and cardiac functional changes were related to TG expression of mitochondrially related genes, mutations thereof, and NRTIs.</description><subject>Animals</subject><subject>Anti-HIV Agents - toxicity</subject><subject>Antiretroviral Therapy, Highly Active</subject><subject>Biological and medical sciences</subject><subject>Biotechnology</subject><subject>Cardiomyopathy, Dilated - chemically induced</subject><subject>Cardiomyopathy, Dilated - metabolism</subject><subject>Cardiomyopathy, Dilated - pathology</subject><subject>Cell Line</subject><subject>DNA, Mitochondrial - analysis</subject><subject>DNA, Mitochondrial - metabolism</subject><subject>Echocardiography</subject><subject>Female</subject><subject>Fundamental and applied biological sciences. Psychology</subject><subject>Heart Ventricles - chemistry</subject><subject>Heart Ventricles - drug effects</subject><subject>Heart Ventricles - metabolism</subject><subject>Human immunodeficiency virus</subject><subject>Hypertrophy, Left Ventricular - chemically induced</subject><subject>Hypertrophy, Left Ventricular - diagnostic imaging</subject><subject>Hypertrophy, Left Ventricular - metabolism</subject><subject>Indinavir - toxicity</subject><subject>Investigative techniques, diagnostic techniques (general aspects)</subject><subject>Laboratory Medicine</subject><subject>Lamivudine - toxicity</subject><subject>Male</subject><subject>Medical sciences</subject><subject>Medicine</subject><subject>Medicine & Public Health</subject><subject>Mice</subject><subject>Mice, Transgenic</subject><subject>Mitochondria, Heart - drug effects</subject><subject>Mitochondria, Heart - metabolism</subject><subject>Mitochondria, Heart - ultrastructure</subject><subject>Myocytes, Cardiac - drug effects</subject><subject>Myocytes, Cardiac - metabolism</subject><subject>Myocytes, Cardiac - ultrastructure</subject><subject>Pathology</subject><subject>Phosphorylation</subject><subject>research-article</subject><subject>Reverse Transcriptase Inhibitors - toxicity</subject><subject>Thymidine Kinase - genetics</subject><subject>Thymidine Kinase - metabolism</subject><subject>Zidovudine - toxicity</subject><issn>0023-6837</issn><issn>1530-0307</issn><fulltext>true</fulltext><rsrctype>article</rsrctype><creationdate>2009</creationdate><recordtype>article</recordtype><sourceid>EIF</sourceid><sourceid>BENPR</sourceid><recordid>eNp9kU9v1DAQxS0EokvhC3BAERLilGX8L3E4VKpKC0gFLhVXy-tMtq6y9mInlfrtmdWutsCBg2VL7zfjN_MYe81hyUGaD6NbhXiPZVoKALPkgj9hC64l1CChfcoWAELWjZHtCXtRyh0AV6rRz9kJ76DtpNAL9vPbnEPEyrvcB-erzfTp-_nHCocB_VSqNFRTdrGsMQYSXQzbeXRTSHEnxdmPmErosdrepkInP-zVl-zZ4MaCrw73Kbu5ury5-FJf__j89eL8uvZayqmWjZK9MthKpYQwnWlEr03rtXK9Uaan54ACTKcMmJVsBtSNgw44tGalnTxlZ_u223m1wd5jJLej3eawcfnBJhfs30oMt3ad7q1ojKalUYP3hwY5_ZpplXYTisdxdBHTXGyrlSEjRhP59h_yLs050nBWCCDvSrUEiT3kcyol43C0wsHuMrPHzOwuM0uZUdGbP4d4LDmERMC7A-CKd-NAgfhQjpzgnGYRHXFyzxWS4hrzo8X_fP8bXMyztg</recordid><startdate>20090201</startdate><enddate>20090201</enddate><creator>Kohler, James J</creator><creator>Hosseini, Seyed H</creator><creator>Cucoranu, Ioan</creator><creator>Hoying-Brandt, Amy</creator><creator>Green, Elgin</creator><creator>Johnson, David</creator><creator>Wittich, Bree</creator><creator>Srivastava, Jaya</creator><creator>Ivey, Kristopher</creator><creator>Fields, Earl</creator><creator>Russ, Rodney</creator><creator>Raper, C Michael</creator><creator>Santoianni, Robert</creator><creator>Lewis, William</creator><general>Nature Publishing Group US</general><general>Nature Publishing Group</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>3V.</scope><scope>7QL</scope><scope>7QP</scope><scope>7QR</scope><scope>7T5</scope><scope>7T7</scope><scope>7TK</scope><scope>7TM</scope><scope>7U9</scope><scope>7X7</scope><scope>7XB</scope><scope>88E</scope><scope>8AO</scope><scope>8C1</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>C1K</scope><scope>CCPQU</scope><scope>DWQXO</scope><scope>FR3</scope><scope>FYUFA</scope><scope>GHDGH</scope><scope>GNUQQ</scope><scope>H94</scope><scope>HCIFZ</scope><scope>K9.</scope><scope>LK8</scope><scope>M0S</scope><scope>M1P</scope><scope>M7N</scope><scope>M7P</scope><scope>P64</scope><scope>PQEST</scope><scope>PQQKQ</scope><scope>PQUKI</scope><scope>PRINS</scope><scope>7QO</scope><scope>5PM</scope></search><sort><creationdate>20090201</creationdate><title>Murine cardiac mtDNA: effects of transgenic manipulation of nucleoside phosphorylation</title><author>Kohler, James J ; Hosseini, Seyed H ; Cucoranu, Ioan ; Hoying-Brandt, Amy ; Green, Elgin ; Johnson, David ; Wittich, Bree ; Srivastava, Jaya ; Ivey, Kristopher ; Fields, Earl ; Russ, Rodney ; Raper, C Michael ; Santoianni, Robert ; Lewis, William</author></sort><facets><frbrtype>5</frbrtype><frbrgroupid>cdi_FETCH-LOGICAL-c533t-3643d48e73442289862d587c54ad848d87cfe20894808b36fe56a0901078b5a3</frbrgroupid><rsrctype>articles</rsrctype><prefilter>articles</prefilter><language>eng</language><creationdate>2009</creationdate><topic>Animals</topic><topic>Anti-HIV Agents - toxicity</topic><topic>Antiretroviral Therapy, Highly Active</topic><topic>Biological and medical sciences</topic><topic>Biotechnology</topic><topic>Cardiomyopathy, Dilated - chemically induced</topic><topic>Cardiomyopathy, Dilated - metabolism</topic><topic>Cardiomyopathy, Dilated - pathology</topic><topic>Cell Line</topic><topic>DNA, Mitochondrial - analysis</topic><topic>DNA, Mitochondrial - metabolism</topic><topic>Echocardiography</topic><topic>Female</topic><topic>Fundamental and applied biological sciences. Psychology</topic><topic>Heart Ventricles - chemistry</topic><topic>Heart Ventricles - drug effects</topic><topic>Heart Ventricles - metabolism</topic><topic>Human immunodeficiency virus</topic><topic>Hypertrophy, Left Ventricular - chemically induced</topic><topic>Hypertrophy, Left Ventricular - diagnostic imaging</topic><topic>Hypertrophy, Left Ventricular - metabolism</topic><topic>Indinavir - toxicity</topic><topic>Investigative techniques, diagnostic techniques (general aspects)</topic><topic>Laboratory Medicine</topic><topic>Lamivudine - toxicity</topic><topic>Male</topic><topic>Medical sciences</topic><topic>Medicine</topic><topic>Medicine & Public Health</topic><topic>Mice</topic><topic>Mice, Transgenic</topic><topic>Mitochondria, Heart - drug effects</topic><topic>Mitochondria, Heart - metabolism</topic><topic>Mitochondria, Heart - ultrastructure</topic><topic>Myocytes, Cardiac - drug effects</topic><topic>Myocytes, Cardiac - metabolism</topic><topic>Myocytes, Cardiac - ultrastructure</topic><topic>Pathology</topic><topic>Phosphorylation</topic><topic>research-article</topic><topic>Reverse Transcriptase Inhibitors - 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In the heart, this can deplete mitochondrial (mt) DNA and cause cardiac dysfunction (eg, left ventricle hypertrophy, LVH). Four unique transgenic, cardiac-targeted overexpressors (TGs) were generated to determine their individual impact on native mitochondrial biogenesis and effects of NRTI administration on development of mitochondrial toxicity. TGs included cardiac-specific overexpression of native thymidine kinase 2 (TK2), two pathogenic TK2 mutants (H121N and I212N), and a mutant of mtDNA polymerase, pol-
γ
(Y955C). Each was treated with antiretrovirals (AZT-HAART, 3 or 10 weeks, zidovudine (AZT) + lamivudine (3TC) + indinavir, or vehicle control). Parameters included left ventricle (LV) performance (echocardiography), LV mtDNA abundance (real-time PCR), and mitochondrial fine structure (electron microscopy, EM) as a function of duration of treatment and presence of TG. mtDNA abundance significantly decreased in Y955C TG, increased in TK2 native and I212N TGs, and was unchanged in H121N TGs at 10 weeks regardless of treatment. Y955C and I212N TGs exhibited LVH during growth irrespective of treatment. Y955C TGs exhibited cardiomyopathy (CM) at 3 and 10 weeks irrespective of treatment, whereas H121N and I212N TGs exhibited CM only after 10 weeks AZT-HAART. EM features were consistent with cardiac dysfunction. mtDNA abundance and cardiac functional changes were related to TG expression of mitochondrially related genes, mutations thereof, and NRTIs.</abstract><cop>New York</cop><pub>Nature Publishing Group US</pub><pmid>19079325</pmid><doi>10.1038/labinvest.2008.121</doi><tpages>9</tpages><oa>free_for_read</oa></addata></record> |
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| subjects | Animals Anti-HIV Agents - toxicity Antiretroviral Therapy, Highly Active Biological and medical sciences Biotechnology Cardiomyopathy, Dilated - chemically induced Cardiomyopathy, Dilated - metabolism Cardiomyopathy, Dilated - pathology Cell Line DNA, Mitochondrial - analysis DNA, Mitochondrial - metabolism Echocardiography Female Fundamental and applied biological sciences. Psychology Heart Ventricles - chemistry Heart Ventricles - drug effects Heart Ventricles - metabolism Human immunodeficiency virus Hypertrophy, Left Ventricular - chemically induced Hypertrophy, Left Ventricular - diagnostic imaging Hypertrophy, Left Ventricular - metabolism Indinavir - toxicity Investigative techniques, diagnostic techniques (general aspects) Laboratory Medicine Lamivudine - toxicity Male Medical sciences Medicine Medicine & Public Health Mice Mice, Transgenic Mitochondria, Heart - drug effects Mitochondria, Heart - metabolism Mitochondria, Heart - ultrastructure Myocytes, Cardiac - drug effects Myocytes, Cardiac - metabolism Myocytes, Cardiac - ultrastructure Pathology Phosphorylation research-article Reverse Transcriptase Inhibitors - toxicity Thymidine Kinase - genetics Thymidine Kinase - metabolism Zidovudine - toxicity |
| title | Murine cardiac mtDNA: effects of transgenic manipulation of nucleoside phosphorylation |
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