Institute of NeuroImmune Pharmacology, Seton Hall University, South Orange, NJ 07079, USA.
Department of Biological Sciences, Seton Hall University, South Orange, NJ 07079, USA.
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。
