Murine cardiac mtDNA: effects of transgenic manipulation of nucleoside phosphorylation
Murine cardiac mtDNA: effects of transgenic manipulation of nucleoside phosphorylation
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DOI：
10.1038/labinvest.2008.121
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发表时间：
2009-02-01
影响因子：
5
通讯作者：
Lewis, William
中科院分区：
文献类型：
--
作者：
Kohler, James J.;Hosseini, Seyed H.;Lewis, William
嘧啶核苷逆转录酶抑制剂（NRTI）对HIV/AIDS的线粒体毒性。在心脏中，这可以耗尽线粒体（mt）DNA并导致心脏功能障碍（例如，左心室肥大，LVH）。产生了四种独特的转基因心脏靶向过表达子（TG），以确定其对天然线粒体生物发生的个体影响以及NRTI给药对线粒体毒性发展的影响。TG包括天然胸苷激酶2（TK 2）的心脏特异性过表达，两种致病性TK 2突变体（H121 N和I212 N），以及mtDNA聚合酶突变体pol-gamma（Y 955 C）。每一组均接受抗逆转录病毒药物治疗（AZT-HAART，3周或10周，齐多夫定（AZT）+拉米夫定（3 TC）+茚地那韦，或溶剂对照）。参数包括左心室（LV）性能（超声心动图），LV mtDNA丰度（实时PCR）和线粒体精细结构（电子显微镜，EM）作为治疗持续时间和TG存在的函数。无论治疗如何，10周时Y 955 C TG中的线粒体DNA丰度显着降低，TK 2天然和I212 N TG中的线粒体DNA丰度增加，而H121 N TG中的线粒体DNA丰度无变化。Y 955 C和I212 N TG在生长期间表现出LVH，与处理无关。Y 955 C TG在3周和10周时表现出心肌病（CM），而H121 N和I212 N TG仅在10周AZT-HAART后表现出CM。EM特征与心功能不全一致。线粒体DNA丰度和心功能变化与TG表达的相关基因，其突变，NRTIs。实验室调查（2009）89，122-130; doi：10.1038/labinvest.2008.121; 2008年12月15日在线发表
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-gamma (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. Laboratory Investigation (2009) 89, 122-130; doi: 10.1038/labinvest.2008.121; published online 15 December 2008