Involvement of MicroRNAs in Hydrogen Peroxide-mediated Gene Regulation and Cellular Injury Response in Vascular Smooth Muscle Cells
RNA and Cardiovascular Research Laboratory, Department of Anesthesiology, New Jersey Medical School, University of Medicine and Dentistry of New Jersey, Newark, New Jersey 07101, USA. Journal of Biological Chemistry
(Impact Factor: 4.57).
02/2009; 284(12):7903-13. DOI: 10.1074/jbc.M806920200
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.
Available from: Rafael Valencia
- "The ROS induction resulted in up-regulation of a specific set of miRNAs, including miR-9, miR-125b, and miR-128 (Lukiw and Pogue, 2007). Lin et al. (2009), and Cheng et al. (2009), found that hydrogen peroxide induce up-regulation of miR-21. "
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ABSTRACT: The identification of aflatoxins as human carcinogens has stimulated extensive research efforts, which continue to the present, to assess potential health hazards resulting from contamination of the human food supply and to minimize exposure. The use of biomarkers that are mechanistically supported by toxicological studies will be important tools for identifying stages in the progression of development of the health effects of environmental agents. miRNAs are small non-coding mRNAs that regulate post-transcriptional gene expression. Also, they are molecular markers of cellular responses to various chemical agents. Growing evidence has demonstrated that environmental chemicals can induce changes in miRNA expression. miRNAs are good biomarkers because they are well defined, chemically uniform, restricted to a manageable number of species, and stable in cells and in the circulation. miRNAs have been used as serological markers of HCC and other tumors. The expression patterns of different miRNAs can distinguish among HCC-hepatitis viruses related, HCC cirrhosis-derivate, and HCC unrelated to either of them. The main objective of this review is to find unreported miRNAs in HCC related to other causes, so that they can be used as specific molecular biomarkers in populations exposed to aflatoxins and as early markers of exposure, damage/presence of HCC. Until today specific miRNAs as markers for aflatoxins-exposure and their reliability are currently lacking. Based on their elucidated mechanisms of action, potential miRNAs that could serve as possible markers of HCC by exposure to aflatoxins are miR-27a, miR-27b, miR-122, miR-148, miR-155, miR-192, miR-214, miR-221, miR-429, and miR-500. Future validation for all of these miRNAs will be needed to assess their prognostic significance and confirm their relationship with the induction of HCC due to aflatoxin exposure.
Available from: PubMed Central
- "As a tumor suppressor, PDCD4 inhibits the oncogenesis and progression of cancers and improves the sensitivity of tumor cells to chemotherapy . In the cardiovascular system, PDCD4 was found mainly as an inducer of apoptosis and a suppressor of proliferation –. Here in HUVECs, PDCD4 is shown to be an inducer of both proliferation and apoptosis. "
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ABSTRACT: We recently found low level of tumor suppressor programmed cell death 4 (PDCD4) associated with reduced atherosclerotic plaque area (unpublished). We investigated whether atheroprotective unidirectional pulsatile shear stress affects the expression of PDCD4 in endothelial cells.
En face co-immunostaining of the mouse aortic arch revealed a low level of PDCD4 in endothelial cells undergoing pulsatile shear stress. Application of unidirectional pulsatile shear stress to human umbilical vein endothelial cells (HUVECs) decreased PDCD4 protein but not mRNA level. Immunoprecipitation revealed that pulsatile shear stress induced the coupling of ubiquitin with PDCD4 expression. The phosphatidyl inositol 3-kinase (PI3K)/Akt pathway was involved in this ubiquitin-proteasome-mediated degradation of PDCD4. Gain of function and loss of function experiments showed that PDCD4 induced turnover (proliferation and apoptosis) of HUVECs. Low PDCD4 level was associated with reduced proliferation but not apoptosis or phosphorylation of endothelial nitric oxide synthase caused by pulsatile shear stress to help maintain the homeostasis of endothelial cells.
Pulsatile shear stress induces ubiquitin-proteasome-mediated degradation of PDCD4 via a PI3K/Akt pathway in HUVECs. PDCD4 induces turnover (proliferation and apoptosis) of HUVECs. Low PDCD4 level is associated with reduced proliferation for maintenance of HUVEC homeostasis under pulsatile shear stress.
Available from: Namrata Rastogi
- "Thus, these results suggested that 6G-induced miR-27b inhibits PPARγ. The inflammatory transcription factor NF-κB physically interacts with PPARγ and upregulates inflammatory cytokines (such as IL-1A, IL-6, JAK2, and IL- 1B) to promote carcinogenesis . Therefore we further examined the roles of miR-27b and PPARγ in the regulation of the oncogenic inflammatory response. "
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ABSTRACT: The natural polyphenolic alkanone, (6)-Gingerol (6G) has established anti-inflammatory and anti-tumoral properties. However, its precise mechanism of action in myeloid leukemia cells is unclear. In this study, we investigated the effects of 6G on myeloid leukemia cells in vitro and in vivo. The results of the present study showed that 6G inhibited proliferation of myeloid leukemia cell lines and primary myeloid leukemia cells while sparing the normal peripheral blood mononuclear cells (PBMCs), in a concentration and time dependent manner. Mechanistic studies using U937 and K562 cell lines revealed that 6G treatment induced ROS generation by inhibiting the mitochondrial respiratory complex-I (MRC-I) which in turn increased the expression of the oxidative stress response associated microRNA, miR-27b and DNA damage. Elevated miR-27b expression inhibited PPARγ with subsequent inhibition of the inflammatory cytokine gene expression associated with the oncogenic NF-kappaB (NFkB) pathway, while the increased DNA damage led to G2/M cell cycle arrest. The 6G induced effects were abolished in the presence of anti-miR27b or the ROS scavenger NAC. In addition, the results of the in vivo xenograft experiments in mice indicated that 6G treatment inhibited tumor cell proliferation and induced apoptosis in agreement with the in vitro studies. Our data provide new evidence that 6G induced myeloid leukemia cell death is initiated by the reactive oxygen species and mediated through the increase in miR-27b expression and DNA damage. The dual induction of increased miR-27b expression and DNA damage associated cell cycle arrest by 6G may have implications for myeloid leukemia treatment.
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