Department of Convergence IT Engineering, School of Convergence Science and Technology, Medical Science and Engineering Program, Pohang University of Science and Technology (POSTECH), South Korea.
Department of Physiology of the School of Basic Medical Science at Zhejiang University, China.
Atherosclerosis. 2023 Dec;387:117383. doi: 10.1016/j.atherosclerosis.2023.117383. Epub 2023 Nov 22.
Deficiency in the thiol transferase glutaredoxin 1 (Grx1) in aging mice promotes, in a sexually dimorphic manner, dysregulation of macrophages and atherogenesis. However, the underlying mechanisms are not known. Here we tested the hypothesis that macrophage-restricted overexpression of Grx1 protects atherosclerosis-prone mice against macrophage reprogramming and dysfunction induced by a high-calorie diet (HCD) and thereby reduces the severity of atherosclerosis.
We generated lentiviral vectors carrying cluster of differentiation 68 (CD68) promoter-driven enhanced green fluorescent protein (EGFP) or Grx1 constructs and conducted bone marrow (BM) transplantation studies to overexpress Grx1 in a macrophage-specific manner in male and female atherosclerosis-prone LDLR mice, and fed these mice a HCD to induce atherogenesis. Atherosclerotic lesion size was determined in both the aortic root and the aorta. We isolated BM-derived macrophages (BMDM) to assess protein S-glutathionylation levels and loss of mitogen-activated protein kinase phosphatase 1 (MKP-1) activity as measures of HCD-induced thiol oxidative stress. We also conducted gene profiling on these BMDM to determine the impact of Grx1 activity on HCD-induced macrophage reprogramming.
Overexpression of Grx1 protected macrophages against HCD-induced protein S-glutathionylation, reduced monocyte chemotaxis in vivo, limited macrophage recruitment into atherosclerotic lesions, and was sufficient to reduce the severity of atherogenesis in both male and female mice. Gene profiling revealed major sex differences in the transcriptional reprogramming of macrophages induced by HCD feeding, but Grx1 overexpression only partially reversed HCD-induced transcriptional reprogramming of macrophages.
Macrophage Grx1 plays a major role in protecting mice atherosclerosis mainly by maintaining the thiol redox state of the macrophage proteome and preventing macrophage dysfunction.
在衰老的小鼠中，硫氧还蛋白谷胱甘肽转移酶 1（Grx1）的缺乏以性别二态的方式促进巨噬细胞的失调和动脉粥样硬化的发生。然而，其潜在机制尚不清楚。在这里，我们检验了这样一个假设，即巨噬细胞特异性过表达 Grx1 可以保护易患动脉粥样硬化的小鼠免受高卡路里饮食（HCD）诱导的巨噬细胞重编程和功能障碍，并因此减轻动脉粥样硬化的严重程度。
我们生成了携带分化群 68（CD68）启动子驱动的增强型绿色荧光蛋白（EGFP）或 Grx1 构建体的慢病毒载体，并进行了骨髓（BM）移植研究，以在雄性和雌性易患动脉粥样硬化的 LDLR 小鼠中特异性过表达 Grx1，然后用 HCD 喂养这些小鼠以诱导动脉粥样硬化形成。在主动脉根部和主动脉中测定动脉粥样硬化病变的大小。我们分离了骨髓来源的巨噬细胞（BMDM）以评估蛋白 S-谷胱甘肽化水平和丝裂原激活的蛋白激酶磷酸酶 1（MKP-1）活性的丧失，作为 HCD 诱导的硫醇氧化应激的指标。我们还对这些 BMDM 进行了基因谱分析，以确定 Grx1 活性对 HCD 诱导的巨噬细胞重编程的影响。
Grx1 的过表达可保护巨噬细胞免受 HCD 诱导的蛋白 S-谷胱甘肽化，减少体内单核细胞趋化性，限制巨噬细胞募集到动脉粥样硬化病变中，并足以减少雌雄小鼠的动脉粥样硬化形成的严重程度。基因谱分析显示，HCD 喂养诱导的巨噬细胞转录重编程在雄性和雌性之间存在主要的性别差异，但 Grx1 的过表达仅部分逆转了 HCD 诱导的巨噬细胞转录重编程。
巨噬细胞 Grx1 通过维持巨噬细胞蛋白质组的硫醇氧化还原状态和防止巨噬细胞功能障碍，在保护小鼠动脉粥样硬化中起着主要作用。
