Methamphetamine and HIV-Tat alter murine cardiac DNA methylation and gene expression.
Methamphetamine and HIV-Tat alter murine cardiac DNA methylation and gene expression.
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甲基苯丙胺和HIV-TAT改变了鼠心脏DNA甲基化和基因表达。
DOI：
10.1016/j.taap.2015.08.012
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发表时间：
2015-11-01
影响因子：
3.8
通讯作者：
Lewis W
中科院分区：
文献类型：
--
作者：
Koczor CA;Fields E;Jedrzejczak MJ;Jiao Z;Ludaway T;Russ R;Shang J;Torres RA;Lewis W
本研究探讨了 HIV-1 和甲基苯丙胺（N-甲基-1-苯丙-2-胺，METH）对 HIV/AIDS 转基因小鼠模型心脏功能障碍的单独和联合影响。冰毒滥用现象十分普遍，并且经常与 HIV-1 感染或艾滋病有关。我们采用微阵列来鉴定 C57Bl/6 野生型同窝小鼠 (WT) 和表达 Tat 的转基因 (TG) 小鼠 METH 给药（10 天，3mg/kg/d，皮下）后心脏左心室 (LV) 基因表达的 mRNA 差异。在 METH 暴露、Tat 表达或两者同时发生后，芯片鉴定出 880 个差异表达基因（表达倍数变化>1.5，p<0.05）。通过通路富集分析，编码钙信号传导和收缩性多肽的 mRNA 在 LV 样本中发生了改变。相关 DNA 甲基化分析显示，METH 暴露和 Tat 表达后，LV DNA 甲基化发生显着变化。通过结合这些数据集，38 个基因启动子（27 个与 METH 相关，11 个与 Tat 相关）在两种分析方法中都表现出差异。其中，只有编码L型钙通道Cav1.2的CACNA1C启动子显示出与其基因表达变化一致的DNA甲基化变化。定量 PCR 证实，使用 METH 后，Cav1.2 LV mRNA 丰度翻倍。 Cav1.2 特异性的相关免疫印迹显示 METH LV 中的蛋白质丰度增加了 3.5 倍。数据表明，Cav1.2 与暴露于 METH 的小鼠左心室钙失调和收缩过度有关。他们认为，METH 暴露对促进左心室功能障碍的致病作用超过了 Tat 引起的作用。
This study addresses the individual and combined effects of HIV-1 and methamphetamine (N-methyl-1-phenylpropan-2-amine, METH) on cardiac dysfunction in a transgenic mouse model of HIV/AIDS. METH is abused epidemically and is frequently associated with acquisition of HIV-1 infection or AIDS. We employed microarrays to identify mRNA differences in cardiac left ventricle (LV) gene expression following METH administration (10d, 3mg/kg/d, subcutaneously) in C57Bl/6 wild-type littermates (WT) and Tat-expressing transgenic (TG) mice. Arrays identified 880 differentially expressed genes (expression fold change>1.5, p<0.05) following METH exposure, Tat expression, or both. Using pathway enrichment analysis, mRNAs encoding polypeptides for calcium signaling and contractility were altered in the LV samples. Correlative DNA methylation analysis revealed significant LV DNA methylation changes following METH exposure and Tat expression. By combining these data sets, 38 gene promoters (27 related to METH, 11 related to Tat) exhibited differences by both methods of analysis. Among those, only the promoter for CACNA1C that encodes L-type calcium channel Cav1.2 displayed DNA methylation changes concordant with its gene expression change. Quantitative PCR verified that Cav1.2 LV mRNA abundance doubled following METH. Correlative immunoblots specific for Cav1.2 revealed a 3.5-fold increase in protein abundance in METH LVs. Data implicate Cav1.2 in calcium dysregulation and hypercontractility in the murine LV exposed to METH. They suggest a pathogenetic role for METH exposure to promote LV dysfunction that outweighs Tat-induced effects.