TRPM7 在 HIV 病毒蛋白存在下酒精诱导的血脑屏障损伤中的作用。
Involvement of TRPM7 in Alcohol-Induced Damage of the Blood-Brain Barrier in the Presence of HIV Viral Proteins.
机构信息
Institute of NeuroImmune Pharmacology, Seton Hall University, South Orange, NJ 07079, USA.
Department of Biological Sciences, Seton Hall University, South Orange, NJ 07079, USA.
出版信息
Int J Mol Sci. 2023 Jan 18;24(3):1910. doi: 10.3390/ijms24031910.
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.
乙醇（EtOH）通过各种蛋白质靶标发挥作用，包括瞬时受体电位 melastatin 7（TRPM7）通道，其在细胞内稳态中发挥重要作用。我们证明 TRPM7 在大鼠脑微血管内皮细胞（rBMVEC）中表达，rBMVEC 是血脑屏障（BBB）的主要细胞成分。大量饮酒常与 HIV 感染有关，但是酒精引起的 BBB 损伤和 HIV 蛋白的机制尚不完全清楚。我们利用 HIV-1 转基因（HIV-1Tg）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，青少年 HIV-1Tg 大鼠的 rBMVEC 中 TRPM7 的表达较低，但对照和 HIV-1Tg 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 TRPM7 的表达。 binge 暴露于乙醇（binge EtOH）以浓度依赖性方式降低对照 rBMVEC 中的 TRPM7 表达，并消除 HIV-1Tg 大鼠中的 TRPM7 表达。在人脑微血管内皮细胞（hBMVEC）中，用乙醇、HIV-1 蛋白和联合处理后，TRPM7 表达下调。接下来，我们使用 BMVECs 构建了体外 BBB 模型，发现 TRPM7 拮抗剂增强了 EtOH 介导的 BBB 完整性变化。我们的研究表明，酒精降低了 TRPM7 的表达，TRPM7 可能参与了 cART 接受者的 HIV-1 患者 BBB 酒精诱导损伤的机制。
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