Abstract

MicroRNAs (miRNAs) comprise a novel class of endogenous, small, noncoding RNAs that negatively regulate approximately 30% of genes in a cell via degradation or translational inhibition of their target mRNAs. However, the effects of reactive oxygen species (ROS) on miRNA expression and the roles of miRNAs in ROS-mediated gene regulation and biological functions of vascular cells are unclear. Using microarray analysis, we demonstrated that miRNAs are aberrantly expressed in vascular smooth muscle cells (VSMCs) after treatment with hydrogen peroxide (H(2)O(2)). H(2)O(2)-mediated up-regulation of microRNA-21 (miR-21) was further confirmed by quantitative real-time PCR. To determine the potential roles of miRNAs in H(2)O(2)-mediated gene regulation and cellular effects, miR-21 expression was down-regulated by miR-21 inhibitor and up-regulated by pre-miR-21. H(2)O(2)-induced VSMC apoptosis and death were increased by miR-21 inhibitor and decreased by pre-miR-21. Programmed cell death 4(PDCD4) was a direct target of miR-21 that was involved in miR-21-mediated effects on VSMCs. Pre-miR-21-mediated protective effect on VSMC apoptosis and death was blocked via adenovirus-mediated overexpression of PDCD4 without the miR-21 binding site. Moreover, activator protein 1 was a downstream signaling molecule of PDCD4 in miR-21-modulated VSMCs. The results suggest that miRNAs in VSMCs are sensitive to H(2)O(2) stimulation. miRN-21 participates in H(2)O(2)-mediated gene regulation and cellular injury response through PDCD4 and the activator protein 1 pathway. miRNAs might play a role in vascular diseases related to ROS.

Highlights

  • The current literature indicates an increasing body of evidence demonstrating that reactive oxygen species (ROS)3 such as superoxide and hydrogen peroxide (H2O2) are involved in Recent studies reveal that post-transcriptional controls of gene expression such as translational regulation are as important as epigenetic and transcriptional controls [15, 16]

  • The results suggest that miRNAs in vascular smooth muscle cells (VSMCs) are sensitive to H2O2 stimulation. miRN-21 participates in H2O2-mediated gene regulation and cellular injury response through Programmed cell death 4 (PDCD4) and the activator protein 1 pathway. miRNAs might play a role in vascular diseases related to ROS

  • The results suggest that Activator protein 1 (AP-1) is a downstream signaling molecule of PDCD4 that might be involved in miR-21-mediated protective effect on VSMCs

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Summary

Introduction

The current literature indicates an increasing body of evidence demonstrating that reactive oxygen species (ROS) such as superoxide and hydrogen peroxide (H2O2) are involved in Recent studies reveal that post-transcriptional controls of gene expression such as translational regulation are as important as epigenetic and transcriptional controls [15, 16]. The effects of ROS on gene expression regulation at the translational level are currently unclear. MiRNAs represent a new layer of gene expression regulators at the translational level, the effects of ROS on miRNA expression and the potential roles of miRNAs in ROS-. MicroRNAs and H2O2 in VSMCs mediated gene regulation and biological functions of vascular cells are unclear. The objective of the current study is to determine the effect of an ROS, H2O2, on miRNA expression in cultured vascular smooth muscle cells (VSMCs) and to determine whether miRNAs play a role in H2O2-mediated effects on gene expression and cellular function

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