Abstract
Background Macrophage-derived foam cells play a central role in atherosclerosis, and their ultimate fate includes apoptosis, promotion of vascular inflammation, or migration to other tissues. Nε-Carboxymethyl-lysine (CML), the key active component of advanced glycation end products, induced foam cell formation and apoptosis. Previous studies have shown that the Vav1/Rac1 pathway affects the macrophage cytoskeleton and cell migration, but its role in the pathogenesis of diabetic atherosclerosis is unknown. Methods and Results In this study, we used anterior tibiofibular vascular samples from diabetic foot amputation patients and accident amputation patients, and histological and cytological tests were performed using a diabetic ApoE−/− mouse model and primary peritoneal macrophages, respectively. The results showed that the atherosclerotic plaques of diabetic foot amputation patients and diabetic ApoE−/− mice were larger than those of the control group. Inhibition of the Vav1/Rac1 pathway reduced vascular plaques and promoted the migration of macrophages to lymph nodes. Transwell and wound healing assays showed that the migratory ability of macrophage-derived foam cells was inhibited by CML. Cytoskeletal staining showed that advanced glycation end products inhibited the formation of lamellipodia in foam cells, and inhibition of the Vav1/Rac1 pathway restored the formation of lamellipodia. Conclusion CML inhibits the migration of foam cells from blood vessels via the Vav1/Rac1 pathway, and this process affects the formation of lamellipodia.
Highlights
The recruitment of macrophages to the intima and phagocytosis of lipids to form foam cells is an essential step in the progression of atherosclerosis [1, 2]
Rahaman et al and Chen et al found that the degree of Vav1 phosphorylation was increased in atherosclerotic plaques, while knocking out Vav1 reduced plaque area [8, 9]; in vitro experiments showed that the loss of the Vav1 gene recovered the migratory ability of oxLDL-induced foam cells [10], but Journal of Immunology Research whether the migration of foam cells is affected by Vav1 gene expression and phosphorylation in diabetes is not clear
This study showed that advanced glycation end products inhibited foam cell migration out of the blood vessels by activating the Vav1/related C3 botulinum toxin substrate 1 (Rac1) pathway and reducing the production of lamellipodia
Summary
Macrophage-derived foam cells play a central role in atherosclerosis, and their ultimate fate includes apoptosis, promotion of vascular inflammation, or migration to other tissues. Nε-Carboxymethyl-lysine (CML), the key active component of advanced glycation end products, induced foam cell formation and apoptosis. Previous studies have shown that the Vav1/Rac pathway affects the macrophage cytoskeleton and cell migration, but its role in the pathogenesis of diabetic atherosclerosis is unknown. Inhibition of the Vav1/Rac pathway reduced vascular plaques and promoted the migration of macrophages to lymph nodes. Cytoskeletal staining showed that advanced glycation end products inhibited the formation of lamellipodia in foam cells, and inhibition of the Vav1/Rac pathway restored the formation of lamellipodia. CML inhibits the migration of foam cells from blood vessels via the Vav1/Rac pathway, and this process affects the formation of lamellipodia
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