Involvement of TRPM7 in Alcohol-Induced Damage of the Blood-Brain Barrier in the Presence of HIV Viral Proteins.
Involvement of TRPM7 in Alcohol-Induced Damage of the Blood-Brain Barrier in the Presence of HIV Viral Proteins.
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DOI：
10.3390/ijms24031910
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发表时间：
2023-01-18
影响因子：
5.6
通讯作者：
Chang SL
中科院分区：
文献类型：
--
作者：
Mack ML;Huang W;Chang SL
乙醇（EtOH）通过各种蛋白质靶点发挥其作用，包括瞬时受体电位melastatin 7（TRPM 7）通道，其在细胞内稳态中发挥重要作用。我们证明了TRPM 7在大鼠脑微血管内皮细胞（rBMVECs）中表达，rBMVECs是血脑屏障（BBB）的主要细胞成分。大量饮酒通常与HIV感染有关，但酒精诱导的BBB损伤和HIV蛋白的潜在机制尚未完全了解。我们利用HIV-1转基因（HIV-1 Tg）大鼠模拟接受联合抗逆转录病毒治疗（cART）的HIV-1患者，并证明与对照动物相比，青春期HIV-1 Tg大鼠rBMVEC中TRPM 7的表达较低，然而，对照和HIV-1 Tg大鼠在9周时表达相似的水平，表明HIV-1蛋白的持续存在延迟了TRPM 7的表达。过量暴露于EtOH（过量EtOH）以浓度依赖性方式降低对照rBMVECs中TRPM 7的表达，并消除HIV-1 Tg大鼠中TRPM 7的表达。在人BMVECs（hBMVECs）中，TRPM 7表达下调后用乙醇，HIV-1蛋白，和组合处理。接下来，我们使用BMVECs构建了体外BBB模型，发现TRPM 7拮抗剂增强了EtOH介导的BBB完整性变化。我们的研究表明，酒精降低TRPM 7表达，TRPM 7可能参与cART的HIV-1患者中BBB酒精诱导损伤的机制。
Ethanol (EtOH) exerts its effects through various protein targets, including transient receptor potential melastatin 7 (TRPM7) channels, which play an essential role in cellular homeostasis. We demonstrated that TRPM7 is expressed in rat brain microvascular endothelial cells (rBMVECs), the major cellular component of the blood–brain barrier (BBB). Heavy alcohol drinking is often associated with HIV infection, however mechanisms underlying alcohol-induced BBB damage and HIV proteins, are not fully understood. We utilized the HIV-1 transgenic (HIV-1Tg) rat to mimic HIV-1 patients on combination anti-retroviral therapy (cART) and demonstrated TRPM7 expression in rBMVECs wass lower in adolescent HIV-1Tg rats compared to control animals, however control and HIV-1Tg rats expressed similar levels at 9 weeks, indicating persistent presence of HIV-1 proteins delayed TRPM7 expression. Binge exposure to EtOH (binge EtOH) decreased TRPM7 expression in control rBMVECs in a concentration-dependent manner, and abolished TRPM7 expression in HIV-1Tg rats. In human BMVECs (hBMVECs), TRPM7 expression was downregulated after treatment with EtOH, HIV-1 proteins, and in combination. Next, we constructed in vitro BBB models using BMVECs and found TRPM7 antagonists enhanced EtOH-mediated BBB integrity changes. Our study demonstrated alcohol decreased TRPM7 expression, whereby TRPM7 could be involved in the mechanisms underlying BBB alcohol-induced damage in HIV-1 patients on cART.
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