Abstract
Metastasis-associated lung adenocarcinoma transcript 1 (MALAT1) plays a crucial role in the pathophysiological process associated with diabetes-related complications. The effect of high glucose levels on macrophage-derived exosomal MALAT1 is unknown. Therefore, we investigated the molecular regulatory mechanisms controlling exosomal MALAT1 in macrophages under high glucose treatment and the therapeutic target of macrophage-derived exosomal MALAT1 using a balloon injury model of vascular disease in diabetic rats. High glucose (25 mM) significantly increased MALAT1 expression in macrophage-derived exosomes. MALAT1 suppressed miR-150-5p expression in macrophage-derived exosomes under high-glucose conditions. Silencing MALAT1 using MALAT1 siRNA significantly reversed miR-150-5p expression induced by macrophage-derived exosomes. Macrophage-derived exosomes under high-glucose treatment significantly increased resistin expression in macrophages. Silencing MALAT1 and overexpression of miR-150-5p significantly decreased resistin expression induced by macrophage-derived exosomes. Overexpression of miR-150-5p significantly decreased resistin luciferase activity induced by macrophage-derived exosomes. Macrophage-derived exosome significantly decreased glucose uptake in macrophages and silencing MALAT1, resistin or overexpression of miR-150-5p significantly reversed glucose uptake. Balloon injury to the carotid artery significantly increased MALAT1 and resistin expression and significantly decreased miR-150-5p expression in arterial tissue. Silencing MALAT1 significantly reversed miR-150-5p expression in arterial tissue after balloon injury. Silencing MALAT1 or overexpression of miR-150-5p significantly reduced resistin expression after balloon injury. In conclusion, high glucose up-regulates MALAT1 to suppress miR-150-5p expression and counteracts the inhibitory effect of miR-150-5p on resistin expression in macrophages to promote vascular disease. Macrophage-derived exosomes containing MALAT1 may serve as a novel cell-free approach for the treatment of vascular disease in diabetes mellitus.
Highlights
Different concentrations of glucose were added to the culture medium for 1 h to explore the effect of high glucose on Metastasis-associated lung adenocarcinoma transcript 1 (MALAT1) expression in macrophage-derived exosomes
We demonstrated that MALAT1 decreased miR-150-5p expression in macrophages under high glucose stimulation
Our study indicates that macrophage-derived exosomes containing MALAT1 may serve as a novel cell-free approach for the treatment of vascular disease caused by diabetes mellitus
Summary
Previous studies have reported that miR-150-5p is the target of MALAT1 in other cell types. An adipokine, has been reported to be secreted from macrophages and plays an important role in atherosclerosis. Macrophage-derived exosomes have been reported to impair beta cell insulin secretion [10]. The effect of hyperglycemia on the regulation of macrophage-derived exosomal MALAT1 and its possible regulatory mechanism in hyperglycemia have not been previously characterized. We hypothesized that there is a link between MALAT1, miR-150-5p, resistin, and atherosclerosis in high glucose status. We investigated the molecular regulatory mechanisms associated with exosomal MALAT1 in macrophages under high glucose treatment and the therapeutic target of macrophage-derived exosomes using a balloon injury model of vascular disease in diabetic rats
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