Njau Florence, Haller Hermann
Division of Nephrology, Hannover Medical School, 30625 Hannover, Germany.
Antioxidants (Basel). 2021 Nov 11;10(11):1798. doi: 10.3390/antiox10111798.
Monocyte-to-macrophage differentiation results in the secretion of various inflammatory mediators and oxidative stress molecules necessary for atherosclerosis pathogenesis. Consequently, this differentiation represents a potential clinical target in atherosclerosis. Calcium dobesilate (CaD), an established vasoactive and angioprotective drug in experimental models of diabetic microvascular complications reduces oxidative stress and inhibits inflammation via diverse molecular targets; however, its effect on monocytes/macrophages is poorly understood. In this study, we investigated the anti-inflammatory mechanism of CaD during phorbol 12-myristate 13-acetate (PMA)-induced monocyte-to-macrophage differentiation in in vitro models of sepsis (LPS) and hyperglycemia, using THP-1 monocytic cell line. CaD significantly suppressed CD14, TLR4, and MMP9 expression and activity, lowering pro-inflammatory mediators, such as IL1β, TNFα, and MCP-1. The effects of CaD translated through to studies on primary human macrophages. CaD inhibited reactive oxygen species (ROS) generation, PKCδ, MAPK (ERK1/2 and p38) phosphorylation, NOX2/p47phox expression, and membrane translocation. We used hydrogen peroxide (H2O2) to mimic oxidative stress, demonstrating that CaD suppressed PKCδ activation via its ROS-scavenging properties. Taken together, we demonstrate for the first time that CaD suppresses CD14, TLR4, MMP9, and signature pro-inflammatory cytokines, in human macrophages, via the downregulation of PKCδ/NADPH oxidase/ROS/MAPK/NF-κB-dependent signaling pathways. Our data present novel mechanisms of how CaD alleviates metabolic and infectious inflammation.
单核细胞向巨噬细胞的分化导致分泌各种动脉粥样硬化发病机制所必需的炎症介质和氧化应激分子。因此，这种分化是动脉粥样硬化潜在的临床靶点。多贝斯钙（CaD）是一种在糖尿病微血管并发症实验模型中已确立的血管活性和血管保护药物，它通过多种分子靶点降低氧化应激并抑制炎症；然而，其对单核细胞/巨噬细胞的作用却知之甚少。在本研究中，我们使用THP - 1单核细胞系，在脓毒症（LPS）和高血糖的体外模型中，研究了多贝斯钙（CaD）在佛波酯12 - 肉豆蔻酸酯13 - 乙酸酯（PMA）诱导的单核细胞向巨噬细胞分化过程中的抗炎机制。CaD显著抑制CD14、TLR4和MMP9的表达及活性，降低促炎介质如IL1β、TNFα和MCP - 1的水平。CaD的这些作用在对原代人巨噬细胞的研究中也得到了验证。CaD抑制活性氧（ROS）生成、PKCδ、丝裂原活化蛋白激酶（ERK1/2和p38）磷酸化、NOX2/p47phox表达及膜转位。我们用过氧化氢（H2O2）模拟氧化应激，证明CaD通过其清除ROS的特性抑制PKCδ活化。综上所述，我们首次证明CaD通过下调PKCδ/烟酰胺腺嘌呤二核苷酸磷酸氧化酶/ROS/丝裂原活化蛋白激酶/核因子κB依赖性信号通路，抑制人巨噬细胞中CD14、TLR4、MMP9和标志性促炎细胞因子的表达。我们的数据揭示了CaD减轻代谢性和感染性炎症的新机制。
