Combined antiretroviral therapy causes cardiomyopathy and elevates plasma lactate in transgenic AIDS mice
Combined antiretroviral therapy causes cardiomyopathy and elevates plasma lactate in transgenic AIDS mice
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DOI：
10.1038/labinvest.3780366
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发表时间：
2001-11-01
影响因子：
5
通讯作者：
Samarel, AM
中科院分区：
文献类型：
--
作者：
Lewis, W;Haase, CP;Samarel, AM
高效抗逆转录病毒治疗(HAART)与心肌病(CM)和艾滋病患者血浆乳酸(LA)升高有关，其机制与线粒体功能障碍有关。为了确定HAART在体内发生的线粒体事件，用HAART联合齐多夫定、拉米夫定和吲哚那韦或赋形剂对照组，对8周龄半合子转基因艾滋病小鼠(NL4-3 Delta gag/pol；TG)和野生型FVB/n窝鼠进行了为期10天或35天的治疗。实验结束时，小鼠进行超声心动图检查，定量心房利钠因子[ANF]和肌浆钙ATPase[SERCA2]的心肌细胞分子标志物丰度，并测定血浆LA。半定量分析心肌组织学特征，并用透射电子显微镜证实结果。在TG+HAART队列治疗35天后，超声心动图显示左心室重量增加了160%。在分子水平上，ANF基因表达增加250%，SERCA2基因表达降低57%。生化方面，LA升高(8.5+/-2.0 mm)。病理上，心肌细胞内可见颗粒状胞浆改变，表明线粒体增大、受损。这些发现在超微结构上得到了证实。在其他队列中没有发现变化。10天后，仅ANF升高，且仅在TG+HAART队列中。结果表明，累积的HAART导致了艾滋病转基因小鼠线粒体CM的LA升高。
Highly active antiretroviral therapy (HAART) is implicated in cardiomyopathy (CM) and in elevated plasma lactate (LA) in AIDS through mechanisms of mitochondrial dysfunction. To determine mitochondrial events from HAART in vivo, 8-week-old hemizygous transgenic AIDS mice (NL4-3 Delta gag/pol; TG) and wild-type FVB/n littermates were treated with the HAART combination of zidovudine, lamivudine, and indinavir or vehicle control for 10 days or 35 days. At termination of the experiments, mice underwent echocardiography, quantitation of abundance of molecular markers of CM (ventricular mRNA encoding atrial natriuretic factor [ANF] and sarcoplasmic calcium ATPase [SERCA2]), and determination of plasma LA. Myocardial histologic features were analyzed semiquantitatively and results were confirmed by transmission electron microscopy. After 35 days in the TG + HAART cohort, left ventricular mass increased 160% by echo cardiography. Molecularly, ANF mRNA increased 250% and SERCA2 mRNA decreased 57%. Biochemically, LA was elevated (8.5 +/- 2.0 mm). Pathologically, granular cytoplasmic changes were found in cardiac myocytes, indicating enlarged, damaged mitochondria. Findings were confirmed ultrastructurally. No changes were found in other cohorts. After 10 days, only ANF was elevated, and only in the TG + HAART cohort. Results show that cumulative HAART caused mitochondrial CM with elevated LA in AIDS transgenic mice.