Abstract
Background3-(5'-Hydroxymethyl-2'-furyl)-1-benzylindazole (YC-1) is a potential anticancer drug that may activate soluble guanylyl cyclase (sGC) and increase the level of cyclic guanosine monophosphate (cGMP). The aim of this study was to explore the effects of YC-1 on lipid droplet accumulation and foam cell formation in macrophages.ResultsHuman-oxidized low density lipoprotein (ox-LDL) was used to induce accumulation of lipid droplets in a murine macrophage cell line, RAW 264.7. Oil red O staining showed that treatment with 20 μM YC-1 for 24 h increased the area of intracellular lipid droplets in macrophages. The results of high content screening (HCS) with the AdipoRed™ assay further revealed that YC-1 enhanced ox-LDL-induced foam cell formation. This was evidenced by an increase in the total area of lipid droplets and the mean fluorescence intensity per cell. Inhibition of cGMP-dependent protein kinase (PKG) using KT5823 significantly reduced YC-1-enhanced lipid droplet formation in ox-LDL-induced macrophage foam cells.ConclusionYC-1 induces lipid droplet formation in macrophages, possibly through the sGC/cGMP/PKG signaling pathway. This chemical should be tested with caution in future clinical trials.
Highlights
Derived from monocytes, macrophages display tissuespecific phenotypes in different locations of the human body [1]
We found that macrophages treated with 10, 20, and 30 μM 3-(5'-Hydroxymethyl-2'-furyl)-1benzyl indazole (YC-1) for 24 h displayed a significant increase in the area of intracellular lipid droplets and total lipid content compared to the control group, as detected and quantified by oil red O staining (Fig. 1a and c)
We found that macrophages treated with 20 μM YC-1 for 12, 24 or 48 h displayed a significant increase in lipid droplet accumulation (Fig. 2a and c)
Summary
Derived from monocytes, macrophages display tissuespecific phenotypes in different locations of the human body [1]. Macrophages regulate various aspects of normal physiology, including development, tissue homoeostasis, remodeling and repair [2]. Several reports have shown that these cells are involved in pathological situations, especially in the initiation of the immune response, the engulfing of pathogens and the progression of atherosclerosis [3]. Low density lipoprotein (LDL) in the plasma penetrates the artery wall and becomes oxidized to oxidized-LDL (ox-LDL), which is phagocytosed by macrophages, leading to the formation of foam cells from macrophages [4]. We have reported that YC-1 can inhibit oleate-induced lipid accumulation in macrophages [9]. Elevated cGMP activates cGMP-dependent protein kinase (PKG) and downstream signal transduction to regulate many cellular responses [11]. Studies have demonstrated several effects of YC-1 on macrophages, including its ability to potentiate the release of tumor necrosis factor-α and nitric oxide production in alveolar macrophages [12, 13]
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