Transgenic cardiac-targeted overexpression of human thymidylate kinase View Full Text


Ontology type: schema:ScholarlyArticle      Open Access: True


Article Info

DATE

2010-03

AUTHORS

James J Kohler, Seyed H Hosseini, Ioan Cucoranu, Olga Zhelyabovska, Elgin Green, Kristopher Ivey, Allison Abuin, Earl Fields, Amy Hoying, Rodney Russ, Robert Santoianni, C Michael Raper, Qinglin Yang, Arnon Lavie, William Lewis

ABSTRACT

Thymidylate kinase (TMPK) is a nucleoside monophosphate kinase that catalyzes phosphorylation of thymidine monophosphate to thymidine diphosphate. TMPK also mediates phosphorylation of monophosphates of thymidine nucleoside analog (NA) prodrugs on the pathway to their active triphosphate antiviral or antitumor moieties. Novel transgenic mice (TG) expressing human (h) TMPK were genetically engineered using the alpha-myosin heavy chain promoter to drive its cardiac-targeted overexpression. In '2 by 2' protocols, TMPK TGs and wild-type (WT) littermates were treated with the NA zidovudine (a deoxythymidine analog, 3'-azido-3'deoxythymidine (AZT)) or vehicle for 35 days. Alternatively, TGs and WTs were treated with a deoxycytidine NA (racivir, RCV) or vehicle. Changes in mitochondrial DNA (mtDNA) abundance and mitochondrial ultrastructure were defined quantitatively by real-time PCR and transmission electron microscopy, respectively. Cardiac performance was determined echocardiographically. Results showed TMPK TGs treated with either AZT or RCV exhibited decreased cardiac mtDNA abundance. Cardiac ultrastructural changes were seen only with AZT. AZT-treated TGs exhibited increased left ventricle (LV) mass. In contrast, LV mass in RCV-treated TGs and WTs remained unchanged. In all cohorts, LV end-diastolic dimension remained unchanged. This novel cardiac-targeted overexpression of hTMPK helps define the role of TMPK in mitochondrial toxicity of antiretrovirals. More... »

PAGES

383

Identifiers

URI

http://scigraph.springernature.com/pub.10.1038/labinvest.2009.146

DOI

http://dx.doi.org/10.1038/labinvest.2009.146

DIMENSIONS

https://app.dimensions.ai/details/publication/pub.1000272049

PUBMED

https://www.ncbi.nlm.nih.gov/pubmed/20065942


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