A Potential Target for Diabetic Vascular Damage: High Glucose-Induced Monocyte Extracellular Vesicles Impair Endothelial Cells by Delivering miR-142-5p

Abstract

Endothelial dysfunction is a key accessory to diabetic cardiovascular complications, and the regulatory role of the extracellular vesicles (EVs) from the innate immune system is growing. We tested whether EVs derived from high glucose-induced monocytes could shuttle microRNAs and impair endothelial cells. EVs from high glucose- and basal glucose-treated THP-1 cells (HG-THP-1 EVs and BG-THP-1 EVs) were isolated and identified. After coculture with THP-1 EVs, human umbilical vein endothelial cells (HUVECs) were tested by proliferation, migration, reactive oxygen species (ROS) detection assays, and western blot for Nrf2/NLRP3 signaling. MiR-142-5p was predicted by miRNAs databases and further verified by RT–qPCR and dual-luciferase reporter gene assays that inhibit Nrf2 expression. The regulation of miR-142-5p in HUVECs was further evaluated. A type 1 diabetes mellitus (T1DM) mouse model was developed for miR-142-5p inhibition. Aorta tissue was harvested for hematoxylin-eosin staining and immunohistochemistry of interleukin-1β (IL-1β). Compared to BG-THP-1 EVs, HG-THP-1 EVs significantly reduced migration and increased ROS production in HUVECs but did not affect proliferation. HG-THP-1 EVs induced suppression of Nrf2 signaling and NLRP3 signaling activation. RT–qPCR results showed that HG-THP-1 EVs overexpressed miR-142-5p in HUVECs. The transfection of miR-142-5p mimics into HUVECs exhibited consistent regulatory effects on HG-THP-1 EVs, whereas miR-142-5p inhibitors demonstrated protective effects. The miR-142-5p antagomir significantly reduced the IL-1β level in T1DM aortas despite morphological changes. To conclude, miR-142-5p transferred by high glucose-induced monocyte EVs participates in diabetic endothelial damage. The inhibition of miR-142-5p could be a potential adjuvant to diabetic cardiovascular protection.

Role of Exosomal miR-205-5p Cargo in Angiogenesis and Cell Migration

“…Particularly, hypoxia and hyperglycemia not only increase sEVs release but also modify its content, affecting neighboring cells [16,17]. This phenomenon has been associated with the promotion of critical physiological and pathological processes such as autophagy, cell migration, angiogenesis, and endothelial dysfunction [18][19][20]. Fitting with this, we demonstrate how HG exposure significantly increases sEVs release from ARPE-19 cells similarly to other oxidative challenges [9,15,16,[21][22][23].…”

The role of oxidative stress in diabetes mellitus-induced vascular endothelial dysfunction

“…Besides, miR-34a was elevated in renal tissue of diabetic kidney disease (DKD) and increased the levels of ROS and inflammation in human renal glomerular endothelial cells by inhibiting the expression of autophagy-related gene 4B (ATG4B), which might contribute to the pathogenesis of DKD [ 97 ]. Notably, miR-142-5p delivered by high glucose-induced monocyte extracellular vesicles reduced migration and increased ROS production in HUVECs and inhibition of miR-142-5p alleviated inflammation in T1DM mice aortas [ 98 ]. In a word, these studies suggest that inhibition or activation of microRNAs could be a potential adjuvants to diabetic vascular therapy.…”

Epigenetic regulation in metabolic diseases: mechanisms and advances in clinical study

“…Moreover, researchers revealed that exosomal miR-142-5p is participated in the pathogenesis of vascular damage by targeting IL-1β. 238 Obesity: miRNA can be a vital regulator for the pathogenesis of obesity. Zhang et al 239 performed RNA sequencing and found that miR-342-3p and its host gene Evl, which are co-expressed in the hypothalamic arcuate nucleus neurons, are increased in the brain and adipose tissues of mice with diet-induced obesity.…”