Hypoxia-Responsive MicroRNA-101 Promotes Angiogenesis <i>via</i> Heme Oxygenase-1/Vascular Endothelial Growth Factor Axis by Targeting Cullin 3

Kim, Jihee; Lee, Kwang Soon; Lee, Dong Hoon; Kim, Joohwan; Kwak, Su Nam; Ha, Kwon Soo; Choe, Jongseon; Won, Moo Ho; Cho, Byung Ryul; Jeoung, Dooil; Lee, Hansoo; Kwon, Young Guen; Kim, Young Myeong

doi:10.1089/ars.2014.5856

Cited by 82 publications

(55 citation statements)

References 61 publications

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“…In this study, we consistently found that the expression of miR-101a was down-regulated in post-infarct rat hearts and cultured neonatal CFs treated with hypoxia. In contrast, a recent study [33] demonstrated that miR-101 was increased in human umbilical vein endothelial cells (HUVECs) exposed to hypoxic conditions and stimulated angiogenesis as a means of improving post-ischemic vascular remodeling in mouse ischemic hind limbs. These results suggest that hypoxia-induced expression of miR-101 may depend on the cell type involved.…”

Section: Discussionmentioning

confidence: 98%

MicroRNA-101a Inhibits Cardiac Fibrosis Induced by Hypoxia via Targeting TGFβRI on Cardiac Fibroblasts

Zhao¹,

Wang²,

Liao³

et al. 2015

Cell Physiol Biochem

105

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Background/Aims: Hypoxia is a basic pathological challenge that is associated with numerous cardiovascular disorders including aberrant cardiac remodeling. Transforming growth factor beta (TGF-β) signaling pathway plays a pivotal role in mediating cardiac fibroblast (CF) function and cardiac fibrosis. Recent data suggested that microRNA-101a (miR-101a) exerted anti-fibrotic effects in post-infarct cardiac remodeling and improved cardiac function. This study aimed to investigate the potential relationship between hypoxia, miR-101a and TGF-β signaling pathway in CFs. Methods and Results: Two weeks following coronary artery occlusion in rats, the expression levels of both TGFβ1 and TGFβRI were increased, but the expression of miR-101a was decreased at the site of the infarct and along its border. Cultured rat neonatal CFs treated with hypoxia were characterized by the up-regulation of TGFβ1 and TGFβRI and the down-regulation of miR-101a. Delivery of miR-101a mimics significantly suppressed the expression of TGFβRI and p-Smad 3, CF differentiation and collagen content of CFs. These anti-fibrotic effects were abrogated by co-transfection with AMO-miR-101a, an antisense inhibitor of miR-101a. The repression of TGFβRI, a target of miR-101a, was validated by luciferase reporter assays targeting the 3'UTR of TGFβRI. Additionally, we found that overexpression of miR-101a reversed the improved migration ability of CFs and further reduced CF proliferation caused by hypoxia. Conclusion: Our study illustrates that miR-101a exerts anti-fibrotic effects by targeting TGFβRI, suggesting that miR-101a plays a multi-faceted role in modulating TGF-β signaling pathway and cardiac fibrosis.

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Section: Discussionmentioning

confidence: 98%

MicroRNA-101a Inhibits Cardiac Fibrosis Induced by Hypoxia via Targeting TGFβRI on Cardiac Fibroblasts

Zhao¹,

Wang²,

Liao³

et al. 2015

Cell Physiol Biochem

105

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“…For example, several miRs ( e.g., miR-155) can potentially activate HO-1 expression through the downregulation of the transcriptional repressor Bach1. 171–173 Additionally, miR-101 promoted HO-1 expression by targeting the Cullin 3: E3 ubiquitin ligase, resulting in Nrf2 stabilization, 174 whereas miR-200a promoted Nrf2 activation by targeting its cytoplasmic anchor Keap-1. 175 …”

Section: Regulation Of Heme Oxygenase Gene Expressionmentioning

confidence: 99%

Targeting heme oxygenase-1 and carbon monoxide for therapeutic modulation of inflammation

Ryter

Choi

2016

Translational Research

304

224

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The heme oxygenase-1 (HO-1) enzyme system remains an attractive therapeutic target for the treatment of inflammatory conditions. HO-1, a cellular stress protein, serves a vital metabolic function as the rate-limiting step in the degradation of heme to generate carbon monoxide (CO), iron, and biliverdin-IXα (BV) which is converted to bilirubin-IXα (BR). HO-1 may function as a pleiotropic regulator of inflammatory signaling programs, through the generation of its biologically active end-products, namely CO and BV/BR. CO, when applied exogenously, can affect apoptotic, proliferative, and inflammatory cellular programs. Specifically, CO can modulate the production of pro- or anti-inflammatory cytokines and mediators. HO-1/CO may also have immunomodulatory effects with respect to regulating the functions of antigen-presenting cells, dendritic cells, and regulatory T-cells. Therapeutic strategies to modulate HO-1 in disease include the application of natural inducing compounds, as well as gene therapy approaches for the targeted genetic overexpression or knockdown of HO-1. Several compounds have been used therapeutically to inhibit HO activity, including competitive inhibitors of the metalloporphyrin series, or non-competitive isoform-selective derivatives of imidazole-dioxolanes. The end-products of HO activity, BV/BR and CO may be used therapeutically as pharmacological treatments. CO may be applied by inhalation, or through the use of CO releasing molecules (CORMs). This review will discuss HO-1 as a therapeutic target in diseases involving inflammation, including lung and vascular injury, sepsis, ischemia/reperfusion injury and transplant rejection.

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“…Furthermore, this study demonstrates that Nrf2 activation consequently inhibits the anchorage-independent growth of breast cancer cells in vitro and carcinogen-induced mammary hyperplasia in vivo. Cul3 is an important component of the Keap-1 protein complex that promotes Keap1-dependent Nrf2 ubiquitination and proteasomal degradation [112]. Kim et al demonstrated that Cul3 is a target of miR-101.…”

Section: Interaction Of Mirnas and The Keap1-nrf2 Signaling Pathwaymentioning

confidence: 99%

Epigenetic regulation of Keap1-Nrf2 signaling

Guo

Zhang

et al. 2015

Free Radical Biology and Medicine

212

144

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The kelch-like ECH-associated protein 1 (Keap1)-nuclear factor erythroid 2-related factor 2 (Nrf2) signaling axis serves as a “master regulator” in response to oxidative/electrophilic stresses and chemical insults through the coordinated induction of a wide array of cytoprotective genes. Therefore, activation of Nrf2 is considered to be an important approach for preventing chronic diseases triggered by stresses and toxins, including cancer. Despite extensive studies suggested that the Keap1-Nrf2 signaling pathway is subject to multiple layers of regulation at the transcriptional, translational, and post-translational levels, the potential epigenetic regulation of Nrf2 and Keap1 has begun to be recognized only in recent years. Epigenetic modifications, heritable alterations in gene expression that occur without changes in the primary DNA sequence, have been reported to be profoundly involved in oxidative stress responses. In this review, we discuss the latest findings regarding the epigenetic regulation of Keap1-Nrf2 signaling by DNA methylation, histone modification, and microRNAs. The crosstalk among these epigenetic modifications in the regulation of Keap1-Nrf2 signaling pathways is also discussed. Studies of the epigenetic modification of Nrf2 and Keap1 have not only enhanced our understanding of this complex cellular defense system but have also provided potential new therapeutic targets for the prevention of certain diseases.

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Hypoxia-Responsive MicroRNA-101 Promotes Angiogenesis via Heme Oxygenase-1/Vascular Endothelial Growth Factor Axis by Targeting Cullin 3

Cited by 82 publications

References 61 publications

MicroRNA-101a Inhibits Cardiac Fibrosis Induced by Hypoxia via Targeting TGFβRI on Cardiac Fibroblasts

MicroRNA-101a Inhibits Cardiac Fibrosis Induced by Hypoxia via Targeting TGFβRI on Cardiac Fibroblasts

Targeting heme oxygenase-1 and carbon monoxide for therapeutic modulation of inflammation

Epigenetic regulation of Keap1-Nrf2 signaling

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