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NPC-EXs Alleviate Endothelial Oxidative Stress and Dysfunction through the miR-210 Downstream Nox2 an 时间:2017-06-13 12:04 来源:未知作者:admin 点击: 次 Abstract:We have demonstrated that neural progenitor cells (NPCs) protect endothelial cells (ECs) from oxidative stress. Since exosomes (EXs) can convey the benefit of parent cells through their carried microRNAs (miRs) and miR-210 is ubiquitously expressed with versatile functions, we investigated the role of miR-210 in the effects of NPC-EXs on oxidative stress and dysfunction in ECs. NPCs were transfected with control and miR-210 scramble/inhibitor/mimic to generate NPC-EXscon, NPC-EXssc, NPC-EXsanti-miR-210, and NPC-EXsmiR-210. The effects of various NPC-EXs on angiotensin II- (Ang II-) induced reactive oxygen species (ROS) overproduction, apoptosis, and dysfunction, as well as dysregulation of Nox2, ephrin A3, VEGF, and p-VEGFR2/VEGFR2 in ECs were evaluated. Results showed (1) Ang II-induced ROS overproduction, increase in apoptosis, and decrease in tube formation ability, accompanied with Nox2 upregulation and reduction of p-VEGFR2/VEGFR2 in ECs. (2) Compared to NPC-EXscon or NPC-EXssc, NPC-EXsanti-miR-210 were less whereas NPC-EXsmiR-210 were more effective on attenuating these detrimental effects induced by Ang II in ECs. (3) These effects of NPC-EXsanti-miR-210 and NPC-EXsmiR-210 were associated with the changes of miR-210, ephrin A3, VEGF, and p-VEGFR2/VEGFR2 ratio in ECs. Altogether, the protective effects of NPC-EXs on Ang II-induced endothelial injury through miR-210 which controls Nox2/ROS and VEGF/VEGFR2 signals were studied.
1. Introduction
Oxidative stress is well-known to play a critical role in a diverse array of cardiovascular disorders including hypertension, diabetic vasculopathy, hypercholesterolemia, and atherosclerosis [1–3]. Indeed, overproduction of reactive oxygen species (ROS) has been shown to induce dysfunction, proinflammatory, and apoptotic death of endothelial cells (ECs) [4–6]. Therefore, an efficient antioxidant defense system to prevent endothelial dysfunction is critical in the protection of vasculature.
Recently, neural crest stem cells have been reported to promote the survival of neurons under normal and oxidative stress conditions in a superoxide dismutase 2 mutant neuron cell line [7]. As one type of stem cells in the brain, neural progenitor cells (NPCs) residing in the subventricular zone contact the blood vessels and directly juxtapose to ECs [8]. The two types of cells could interact with each other through direct physical contact or through paracrine mechanisms with potentially different biological effects. As showed in our previous study [9], NPCs can decrease hypoxia/reoxygenation-induced ROS overproduction on ECs. However, the exact mechanism of NPCs against oxidative stress remains unclear. Exosomes (EXs), small vesicles secreted by most cells, are emerging as mediators for cell-cell communications. They can transfer the carried cargoes such as microRNAs (miRs) and proteins to distant/nearby cells and thereby modulate the recipient cell function [10–12]. Stem cell-derived EXs have been shown to convey the benefits of their parent cells [13–17]. For example, endothelial progenitor cell-derived vesicles can protect ECs against hypoxia/reoxygenation injury [16]. Mesenchymal stem cell-derived EXs can promote functional recovery and neurovascular plasticity after stroke in rats through miR-133 [13] and enhance cell survival in kidney injury [17]. More recently, our group demonstrated that endothelial progenitor cell-derived vesicles from healthy controls have protective effects on the function of endothelial progenitor cells from diabetic patients through their carried miR-126 [14]. In order to explore the mechanism of NPCs protecting ECs from oxidative stress, we investigated whether EXs released from NPCs (NPC-EXs) can protect ECs from oxidative stress and dysfunction in an Ang II-induced injury model.
miR-210 is ubiquitously expressed in a wide range of cells, such as inducible pluripotent stem cells and bone marrow stem cells, and has versatile functions [18]. It is reported that miR-210 is a crucial element of ECs in response to hypoxia which considerably influences the endothelial angiogenic capability [19]. More studies have demonstrated that miR-210 not only influences cell survival by targeting apoptotic genes [20–22] but also displays antioxidant effect by reducing mitochondrial ROS production [23–25]. Recently, Wang et al. reported that EXs derived from inducible pluripotent stem cells can deliver miR-210 to the cardiomyocytes and protect the cardiomyocytes against H2O2-induced oxidative stress [15]. Nevertheless, there is no study investigating whether miR-210 is involved in the protective effects of NPC-EXs on ECs against oxidative stress.
In this study, we illustrated whether miR-210 participates in the protective effects of NPC-EXs on attenuating Ang II-induced ROS overproduction and dysfunction in ECs.