Abstract
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.
Highlights
Atherosclerosis is a complex disease with poorly understood mechanisms that contribute to the disease pathogenesis but involve inflammation and oxidative stress
Since phorbol 12-myristate 13-acetate (PMA) treatment induces greater differentiation of THP-1 cells, we studied the effect(s) of Calcium dobesilate (CaD) on PMA-induced monocyte-to-macrophage differentiation
Dose-dependently downregulated TLR4, but not TLR2, expression (Figure 2C,D). These results suggest that CaD selectively inhibits certain aspects of monocyte-to-macrophage differentiation and inflammation
Summary
Atherosclerosis is a complex disease with poorly understood mechanisms that contribute to the disease pathogenesis but involve inflammation and oxidative stress. Monocyte-to-macrophage differentiation associates with high expression of cluster of differentiation (CD) [1,2] and Toll-like Receptor (TLR) [3,4] family members This process results in the activation of enzyme systems involved in reactive oxygen species (ROS) production (i.e., leukocyte NADPH oxidase) [5], leading to oxidative stress that occurs in parallel with pro-inflammatory molecules [6] and matrix metalloproteinases [7,8] activation. All these processes contribute to atherosclerosis initiation and progression. CD14 macrophages are found in complicated atherosclerotic lesions [2], and atherosclerosis progression delays when Nox (an essential component of NADPH oxidase) is inhibited in animal models [9,10]
Sign-in/Register to view highlights & summary Sign-in/Register to access full text options 
Talk to us
Join us for a 30 min session where you can share your feedback and ask us any queries you have
Schedule a callDisclaimer: All third-party content on this website/platform is and will remain the property of their respective owners and is provided on "as is" basis without any warranties, express or implied. Use of third-party content does not indicate any affiliation, sponsorship with or endorsement by them. Any references to third-party content is to identify the corresponding services and shall be considered fair use under The CopyrightLaw.
