Abstract
Background Advanced glycation end products play an important role in diabetic atherosclerosis. The effects of advanced glycation end products (AGEs) on vascular smooth muscle cell- (VSMC-) derived foam cell formation and phenotypic transformation are unknown. Methods Serological and histological samples were obtained from diabetic amputation patients and accident amputation patients from the Affiliated Hospital of Jiangsu University. CD68/Actin Alpha 2 (ACTA2) coimmunofluorescence sections were used to quantify the number of VSMCs with macrophage-like phenotypes. Western blotting was used to detect the expression of the receptor of advanced glycation end products in vascular samples. Enzyme-linked immunosorbent assay (ELISA) was used to evaluate the level of serum Nε-carboxymethyl-lysine (CML). In vitro oil red O staining was used to examine lipid accumulation in VSMCs stimulated by CML. The expression of VSMCs and macrophage markers was measured by western blotting and quantitative real-time PCR. Furthermore, changes in VSMC migration and secretion were detected by the Transwell assay and ELISA. Results In the arterial plaque sections of diabetic patients, VSMCs transformed to a macrophage-like phenotype. The serum CML and RAGE levels in the plaques were significantly higher in the diabetes group than those in the healthy control group and were significantly related to the number of macrophage-like VSMCs. CML stimulation promoted intracellular lipid accumulation. However, CML stimulation decreased the expression of VSMC markers and increased the expression of macrophage phenotype markers. Finally, CML promoted smooth muscle cell migration and the secretion of proinflammatory-related factors. Conclusions CML induces VSMC-derived foam cell formation, and VSMCs transdifferentiate to a macrophage-like state, which may be mediated by the activation of RAGE.
Highlights
Advanced glycation end products play an important role in diabetic atherosclerosis
advanced glycation end products (AGEs) are expressed in diabetes and induce cardiovascular disease complications [15]
Many VSMCs express macrophage markers in the infiltrating site, suggesting that macrophages in plaques are transformed from SMCs, a finding that is consistent with a previous study by Allahverdian et al [7]
Summary
Atherosclerosis is characterized by a low degree of sterile inflammation of the arterial wall. The proportion of macrophages in the plaques is gradually reduced, macrophage markers are detected Because this phenomenon may be due to the recruitment of mononuclear macrophages and redundancy of retention factors, researchers have turned their attention to other cells capable of transforming into macrophages, such as endothelial cells, smooth muscle cells, and progenitor cells, the most important of which are VSMCs [7, 8]. Under in vitro culture conditions or during atherosclerosis, smooth muscle cells undergo a phenotypic transformation: in vitro, the ability to proliferate, migrate, and secrete various extracellular matrices and cytokines is increased [9]. The key active component of advanced glycation end products, Nε-carboxymethyllysine, promotes macrophage expression of CD36 and scavenger receptor class B type 1 (SR-B1) and induces lipid accumulation and foam cell formation, accelerating the progression of atherosclerosis [16]. Our present data suggest that advanced glycation end products induce lipid accumulation in VSMCs and transdifferentiate VSMC to a macrophage-like state
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