Induction of microRNA‐138 by pro‐inflammatory cytokines causes endothelial cell dysfunction

Sen, Anagha; Most, Patrick; Peppel, Karsten

doi:10.1016/j.febslet.2014.01.033

Cited by 38 publications

(31 citation statements)

References 48 publications

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“…Hypoxia/ischemia stimulates EPCs to migrate from the bone marrow into the peripheral blood, adhere to the endothelium at sites of hypoxia/ischemia and participate in new vessel formation by differentiating into ECs (21). miR-138 may be involved in the regulation of hypoxia-induced EC dysfunction (22); however, to the best of our knowledge, the exact role of miR-138 in mediating EPC proliferation under hypoxia has not been studied. The present study demonstrated that miR-138 significantly suppressed the hypoxia-induced proliferation of EPCs, possibly by inducing cell cycle arrest at the G1 stage.…”

Section: Discussionmentioning

confidence: 99%

“…Nishimura et al (23) reported that hypoxia induced the proliferation of tissue-resident EPCs in the lung. Furthermore, Sen et al (22) indicated that exposure to pro-inflammatory cytokines, including angiotensin II, endothelin-1 and tumor necrosis factor, may result in EC dysfunction and the downregulation of S100A1 expression by inducing miR-138 in a manner dependent on the stabilization of HIF-1α. This suggests that miR-138 is involved in EC dysfunction (22).…”

Section: Discussionmentioning

confidence: 99%

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MicroRNA-138 inhibits hypoxia-induced proliferation of endothelial progenitor cells via inhibition of HIF-1α-mediated MAPK and AKT signaling

Zhou

Zeng

Xiong

2017

Experimental and Therapeutic Medicine

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Abstract. Endothelial progenitor cells (EPCs) participate in angiogenesis by differentiating into endothelial cells (ECs)and may be developed to treat ischemia/reperfusion injury. MicroRNAs (miRs) are a type of non-coding RNA that are 18-25 nucleotides in length and serve a role in angiogenesis. It has been demonstrated that miR-138 regulates hypoxia-induced EC dysfunction. However, to the best of our knowledge, the exact role of miR-138 in the regulation of hypoxia-induced EPCs has not previously been reported. In the present study, data collected from an MTT assay indicated that hypoxia treatment enhanced EPC proliferation, which was accompanied by an upregulation of hypoxia-inducible factor 1α (HIF-1α) expression. miR-138 overexpression inhibited hypoxia-induced EPC proliferation and induced cell cycle arrest at the G1 stage. A mechanistic investigation revealed that miR-138 negatively regulated HIF-1α protein levels but did not affect HIF-1α mRNA levels in EPCs. Moreover, results from a dual luciferase reporter assay demonstrated that HIF-1α was a direct target of miR-138 in EPCs. Furthermore, upregulation of miR-138 suppressed the hypoxia-induced upregulation of HIF-1α. Downstream factors of HIF-1α were also investigated and it was observed that the upregulation of miR-138 inhibited the hypoxia-induced upregulation of vascular endothelial growth factor, as well as the activity of mitogen-activated protein kinase and AKT signaling in EPCs. In summary, the present study suggested that miR-138 inhibits hypoxia-induced EPC proliferation, possibly by inhibiting HIF-1α-mediated signaling.

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Section: Discussionmentioning

confidence: 99%

Section: Discussionmentioning

confidence: 99%

MicroRNA-138 inhibits hypoxia-induced proliferation of endothelial progenitor cells via inhibition of HIF-1α-mediated MAPK and AKT signaling

Zhou

Zeng

Xiong

2017

Experimental and Therapeutic Medicine

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“…They induce EC p38 and JNK activation, increase immune cell adhesion molecule expression, promote VSMC migration, and cause EC barrier dysfunction, all of which further accelerate local inflammation (38,39). A number of studies have determined that heparin exhibits anti-inflammatory properties and modulates angiogenesis (1).…”

Section: Discussionmentioning

confidence: 99%

“…TNF␣ has been shown to inhibit endothelial nitrous oxide synthase activity and, as a result, decrease NO production, which would lead to lower levels of active cGMP-dependent protein kinase. This causes ECs to become vasoconstrictive and, eventually, dysfunctional (38,57). Recent studies have shown that the effects of heparin in VSMCs involve cGMP-dependent protein kinase (22).…”

Section: Discussionmentioning

confidence: 99%

Heparin Decreases in Tumor Necrosis Factor α (TNFα)-induced Endothelial Stress Responses Require Transmembrane Protein 184A and Induction of Dual Specificity Phosphatase 1

Farwell

Kanyi

Hamel

et al. 2016

Journal of Biological Chemistry

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Despite the large number of heparin and heparan sulfate binding proteins, the molecular mechanism(s) by which heparin alters vascular cell physiology is not well understood. Studies with vascular smooth muscle cells (VSMCs) indicate a role for induction of dual specificity phosphatase 1 (DUSP1) that decreases ERK activity and results in decreased cell proliferation, which depends on specific heparin binding. The hypothesis that unfractionated heparin functions to decrease inflammatory signal transduction in endothelial cells (ECs) through heparininduced expression of DUSP1 was tested. In addition, the expectation that the heparin response includes a decrease in cytokine-induced cytoskeletal changes was examined. Heparin pretreatment of ECs resulted in decreased TNF␣-induced JNK and p38 activity and downstream target phosphorylation, as identified through Western blotting and immunofluorescence microscopy. Through knockdown strategies, the importance of heparin-induced DUSP1 expression in these effects was confirmed. Quantitative fluorescence microscopy indicated that heparin treatment of ECs reduced TNF␣-induced increases in stress fibers. Monoclonal antibodies that mimic heparin-induced changes in VSMCs were employed to support the hypothesis that heparin was functioning through interactions with a receptor. Knockdown of transmembrane protein 184A (TMEM184A) confirmed its involvement in heparin-induced signaling as seen in VSMCs. Therefore, TMEM184A functions as a heparin receptor and mediates anti-inflammatory responses of ECs involving decreased JNK and p38 activity.For almost 100 years heparin has been used as an anticoagulant. Specific heparin interactions with proteins important in the anti-clotting system are now well understood. Many heparin binding proteins, including quite a few involved in modulating vascular function, inflammation, and angiogenesis, have been identified (reviewed in Ref. 1). The large number of reports indicating evidence of decreased endogenous heparin and heparan sulfates (HS) 3 in atherosclerosis (in model animals and human disease) led to a proposal that decreases in endogenous heparins might be important in the development of atherosclerosis (2). More recent evidence in support of that hypothesis includes increased heparanase expression in atherosclerosis (reviewed in Ref.3) and increased levels of glycocalyx heparan sulfate in regions of the vasculature where laminar flow decreases the likelihood of atherosclerosis development (4).In addition to heparin, heparin binding proteins typically also bind HS chains on HS proteoglycans (HSPGs). Although the carbohydrate backbones of heparin and HS are identical, modifications and sulfation patterns vary. HS chains have fewer sulfate residues per disaccharide and a lower overall charge, but their widespread expression suggests that HS may provide many in vivo functions identified originally as heparin functions (reviewed in Ref. 5). Heparin binding to growth factors modulates their activity and appears to protect them from degradation...

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“…miR-376b was reported to inhibit angiogenesis by targeting the VEGFA/Notch1 signaling pathway . A functional link between upregulation of miR-138 and endothelial dysfunction has also been proposed (Sen et al 2014).…”

Section: Discussionmentioning

confidence: 99%

IGF-1 deficiency in a critical period early in life influences the vascular aging phenotype in mice by altering miRNA-mediated post-transcriptional gene regulation: implications for the developmental origins of health and disease hypothesis

Tarantini

Giles

Wren

et al. 2016

AGE

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Epidemiological findings support the concept of Developmental Origins of Health and Disease, suggesting that early-life hormonal influences during a sensitive period of development have a fundamental impact on vascular health later in life. The endocrine changes that occur during development are highly conserved across mammalian species and include dramatic increases in circulating IGF-1 levels during adolescence. The present study was designed to characterize the effect of developmental IGF-1 deficiency on the vascular aging phenotype. To achieve that goal, early-onset endocrine IGF-1 deficiency was induced in mice by knockdown of IGF-1 in the liver using Cre-lox technology (Igf1 f/f mice crossed with mice expressing albumindriven Cre recombinase). This model exhibits lowcirculating IGF-1 levels during the peripubertal phase of development, which is critical for the biology of aging. Due to the emergence of miRNAs as important regulators of the vascular aging phenotype, the effect of early-life IGF-1 deficiency on miRNA expression profile in the aorta was examined in animals at 27 months of age. We found that developmental IGF-1 deficiency elicits persisting late-life changes in miRNA expression in the vasculature, which significantly differed from AGE (2016) 38:239-258

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Induction of microRNA‐138 by pro‐inflammatory cytokines causes endothelial cell dysfunction

Cited by 38 publications

References 48 publications

MicroRNA-138 inhibits hypoxia-induced proliferation of endothelial progenitor cells via inhibition of HIF-1α-mediated MAPK and AKT signaling

MicroRNA-138 inhibits hypoxia-induced proliferation of endothelial progenitor cells via inhibition of HIF-1α-mediated MAPK and AKT signaling

Heparin Decreases in Tumor Necrosis Factor α (TNFα)-induced Endothelial Stress Responses Require Transmembrane Protein 184A and Induction of Dual Specificity Phosphatase 1

IGF-1 deficiency in a critical period early in life influences the vascular aging phenotype in mice by altering miRNA-mediated post-transcriptional gene regulation: implications for the developmental origins of health and disease hypothesis

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