Abstract
Atherosclerosis (AS) is a chronic inflammatory disorder characterized by endothelial dysfunction. Endothelial progenitor cells (EPCs) can overcome endothelial dysfunction and reduce AS risk. This study focused on the role of EPC-secreted extracellular vesicles (EPC-EVs) in AS. First, mouse EPCs and mouse aortic endothelial cells (MAECs) were isolated and identified. EVs were isolated from EPCs and identified. EPC-EVs were co-cultured with MAECs and the internalization of EVs was observed. Glutathione (GSH) consumption, reactive oxygen species (ROS) production, lipid peroxidation, and iron accumulation and cell death in endothelial cells were detected. The binding relationship between miR-199a-3p and specificity protein 1 (SP1) was confirmed using dual-luciferase and RIP assays. The mouse model of AS was established. The relationships between miR-199a-3p expression and aortic area plaque and serum pro-inflammatory factor were analyzed. The degree of atherosclerotic lesion was detected using oil red O staining and the serum inflammatory factors were detected using ELISA. Our results elicited that EPC-EVs inhibited cell death, GSH consumption, ROS production, lipid peroxidation, and iron accumulation in endothelial cells, thereby suppressing ferroptosis of endothelial cells. EPC-EVs transferred miR-199a-3p into endothelial cells. miR-199a-3p targeted SP1. Silencing miR-199a-3p or overexpression of SP1 in endothelial cells reversed the effect of EPC-EVs on ferroptosis of endothelial cells. In vivo experiments confirmed that EPC-EVs inhibited ferroptosis of endothelial cells and then alleviated the occurrence of AS via the miR-199a-3p/SP1 axis. To conclude, EPC-EVs transferred miR-199a-3p to inhibit SP1, thus repressing ferroptosis of endothelial cells and retarding the occurrence of AS.
Highlights
Atherosclerosis (AS), a chronic inflammatory disorder, is concerned with diverse disease states and multiple risk factors, mainly arterial hypertension, hypercholesterolemia, and diabetes [1]
The results showed that the isolated Endothelial progenitor cells (EPCs)-Extracellular vesicles (EVs) were bilayer vesicles, and the size of separated particles was in the range of 30–300 nm (Fig. 1C, D)
This study found that EPCs secreted EVs to deliver miR-199a-3p to inhibit specificity protein 1 (SP1), thereby inhibiting endothelial cells (ECs) ferroptosis and delaying vascular endothelial injury, and alleviating AS (Fig. 7)
Summary
Atherosclerosis (AS), a chronic inflammatory disorder, is concerned with diverse disease states and multiple risk factors, mainly arterial hypertension, hypercholesterolemia, and diabetes [1]. AS is manifested with the pathological remodeling of arterial wall resulted from lipid accumulation in the sub-endothelial layer of the artery and the retention of lipid leads to inflammatory response [2]. The inflammatory state triggers further endothelial dysfunction and extracellular matrix remodeling, eventually resulting in the formation of calcified and vulnerable plaques [1, 3]. Ferroptosis represents a recently identified regulated cell death, is featured by the iron-dependent lipid hydroperoxide accumulation, which differs from other cell deaths in morphology, biochemistry, and genetics [5]. Inhibition of ferroptosis alleviates AS by attenuating lipid peroxidation and alleviating endothelial dysfunction in aortic endothelial cells (ECs) [6, 8].
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