Department of Immunology, School of Medicine, Yangtze University, Jingzhou 434023, China.
Department of Oncology, Jingzhou Hospital Affiliated to Yangtze University, Jingzhou 434023, China.
Acta Biochim Biophys Sin (Shanghai). 2023 Aug 1;55(9):1496-1505. doi: 10.3724/abbs.2023146.
In atherosclerosis, macrophage-derived foam cell formation is considered to be a hallmark of the pathological process; this occurs via the uptake of modified lipoproteins. In the present study, we aim to determine the role of transaldolase in foam cell formation and atherogenesis and reveal the mechanisms underlying its role. Bone marrow-derived macrophages (BMDMs) isolated from mice successfully form foam cells after treatment with oxidized low-density lipoprotein (80 μg/mL). Elevated transaldolase levels in the foam cell model are assessed by quantitative polymerase chain reaction and western blot analysis. Transaldolase overexpression and knockdown in BMDMs are achieved via plasmid transfection and small interfering RNA technology, respectively. We find that transaldolase overexpression effectively attenuates, whereas transaldolase knockdown accelerates, macrophage-derived foam cell formation through the inhibition or activation of cholesterol uptake mediated by the scavenger receptor cluster of differentiation 36 (CD36) in a p38 mitogen-activated protein kinase (MAPK) signaling-dependent manner. Transaldolase-mediated glutathione (GSH) homeostasis is identified as the upstream regulator of p38 MAPK-mediated CD36-dependent cholesterol uptake in BMDMs. Transaldolase upregulates GSH production, thereby suppressing p38 activity and reducing the CD36 level, ultimately preventing foam cell formation and atherosclerosis. Thus, our findings indicate that the transaldolase-GSH-p38-CD36 axis may represent a promising therapeutic target for atherosclerosis.
在动脉粥样硬化中，巨噬细胞源性泡沫细胞的形成被认为是病理过程的标志；这是通过摄取修饰的脂蛋白发生的。在本研究中，我们旨在确定转醛醇酶在泡沫细胞形成和动脉粥样硬化发生中的作用，并揭示其作用的机制。从小鼠分离的骨髓来源的巨噬细胞（BMDMs）在用氧化的低密度脂蛋白（80μg/ml）处理后成功形成泡沫细胞。通过定量聚合酶链反应和western blot 分析评估泡沫细胞模型中转醛醇酶水平的升高。通过质粒转染和小干扰 RNA 技术分别实现 BMDMs 中转醛醇酶的过表达和敲低。我们发现，转醛醇酶过表达有效地减弱，而转醛醇酶敲低加速，通过 p38 丝裂原活化蛋白激酶（MAPK）信号依赖性方式，通过清道夫受体分化簇 36（CD36）介导的胆固醇摄取的抑制或激活，巨噬细胞源性泡沫细胞的形成。转醛醇酶介导的谷胱甘肽（GSH）动态平衡被确定为 BMDMs 中 p38 MAPK 依赖性 CD36 依赖性胆固醇摄取的上游调节剂。转醛醇酶上调 GSH 的产生，从而抑制 p38 活性并降低 CD36 水平，最终防止泡沫细胞形成和动脉粥样硬化。因此，我们的研究结果表明，转醛醇酶-GSH-p38-CD36 轴可能是动脉粥样硬化的一个有前途的治疗靶点。
