Posttranscriptional and transcriptional regulation of endothelial nitric-oxide synthase during hypoxia: the role of microRNAs

Kalinowski, Leszek; Janaszak-Jasiecka, Anna; Siekierzycka, Anna; Bartoszewska, Sylwia; Woźniak, Marcin; Lejnowski, Dawid; Collawn, James F.; Bartoszewski, Rafał

doi:10.1186/s11658-016-0017-x

Cited by 42 publications

(18 citation statements)

References 104 publications

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“…Although the role of miRNAs in posttranscriptional gene regulation is clearly established, it is now evident that recent specific alterations in miRNA expression can also regulate eNOS levels [ 14 – 18 ] (reviewed in [ 6 ]). Moreover, differences in miRNA expression are also present in cardiovascular disorders [ 38 ], suggesting that miRNA network changes could influence disease pathogenesis.…”

Section: Discussionmentioning

confidence: 99%

eNOS expression and NO release during hypoxia is inhibited by miR-200b in human endothelial cells

et al. 2018

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The nitric oxide (NO) secreted by vascular endothelium is required for the maintenance of cardiovascular homeostasis. Diminished release of NO generated by endothelial NO synthase contributes to endothelial dysfunction. Hypoxia and ischemia reduce endothelial eNOS expression via posttranscriptional mechanisms that result in NOS3 transcript destabilization. Here, we examine whether microRNAs contribute to this mechanism. We followed the kinetics of hypoxia-induced changes in NOS3 mRNA and eNOS protein levels in primary human umbilical vein endothelial cells (HUVECs). Utilizing in silico predictive protocols to identify potential miRNAs that regulate eNOS expression, we identified miR-200b as a candidate. We established the functional miR-200b target sequence within the NOS3 3′UTR, and demonstrated that manipulation of the miRNA levels during hypoxia using miR-200b mimics and antagomirs regulates eNOS levels, and established that miR-200b physiologically limits eNOS expression during hypoxia. Furthermore, we demonstrated that the specific ablation of the hypoxic induction of miR-200b in HUVECs restored eNOS-driven hypoxic NO release to the normoxic levels. To determine whether miR-200b might be the only miRNA that had this effect, we utilized Next Generation Sequencing (NGS) to follow hypoxia-induced changes in the miRNA levels in HUVECS and found 83 novel hypoxamiRs, with two candidate miRNAs besides miR-200b that could potentially influence eNOS levels. Taken together, the data establish miR-200b-eNOS regulation as a first hypoxamiR-based mechanism that limits NO bioavailability during hypoxia in endothelial cells, and show that hypoxamiRs could become useful therapeutic targets for cardiovascular diseases and other hypoxic-related diseases including various types of cancer.Electronic supplementary materialThe online version of this article (10.1007/s10456-018-9620-y) contains supplementary material, which is available to authorized users.

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Section: Discussionmentioning

confidence: 99%

eNOS expression and NO release during hypoxia is inhibited by miR-200b in human endothelial cells

et al. 2018

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“…Indeed, HIF-1, but not HIF-2, is responsible for the transcriptional regulation of the glycolytic pathway enzymes such as phosphofructokinase ( PFK ) and lactate dehydrogenase A ( LDHA ) [ 33 ]. Furthermore, HIF-1 induces genes that are involved in pH regulation (monocarboxylate transporter 4 ( MCT4 ) and carbonic anhydrase 9 ( CA - IX )); in apoptosis induction ( BCL2 /adenovirus E1B 19 kDa-interacting protein 3 ( BNIP3 ) and BCL2/adenovirus E1B 19 kDa-interacting protein 3-like ( BNIP3L/NIX )) [ 17 ]; and in maintaining endothelial homeostasis (endothelial nitric oxide synthase ( NOS3 )) [ 34 ]. Another target of HIF-1 during hypoxia is heme oxygenase-1 ( HMOX1 ) that has pro-angiogenic activity [ 35 ], whereas HIF-2 stimulates the expression of matrix metalloproteinases (MMP) 2 and 13 and the stem cell factor OCT-3/4 [ 17 ].…”

Section: Hif Target Genesmentioning

confidence: 99%

miRNAs regulate the HIF switch during hypoxia: a novel therapeutic target

et al. 2018

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The decline of oxygen tension in the tissues below the physiological demand leads to the hypoxic adaptive response. This physiological consequence enables cells to recover from this cellular insult. Understanding the cellular pathways that mediate recovery from hypoxia is therefore critical for developing novel therapeutic approaches for cardiovascular diseases and cancer. The master regulators of oxygen homeostasis that control angiogenesis during hypoxia are hypoxia-inducible factors (HIFs). HIF-1 and HIF-2 function as transcriptional regulators and have both unique and overlapping target genes, whereas the role of HIF-3 is less clear. HIF-1 governs the acute adaptation to hypoxia, whereas HIF-2 and HIF-3 expressions begin during chronic hypoxia in human endothelium. When HIF-1 levels decline, HIF-2 and HIF-3 increase. This switch from HIF-1 to HIF-2 and HIF-3 signaling is required in order to adapt the endothelium to prolonged hypoxia. During prolonged hypoxia, the HIF-1 levels and activity are reduced, despite the lack of oxygen-dependent protein degradation. Although numerous protein factors have been proposed to modulate the HIF pathways, their application for HIF-targeted therapy is rather limited. Recently, the miRNAs that endogenously regulate gene expression via the RNA interference (RNAi) pathway have been shown to play critical roles in the hypoxia response pathways. Furthermore, these classes of RNAs provide therapeutic possibilities to selectively target HIFs and thus modulate the HIF switch. Here, we review the significance of the microRNAs on the relationship between the HIFs under both physiological and pathophysiological conditions.Electronic supplementary materialThe online version of this article (10.1007/s10456-018-9600-2) contains supplementary material, which is available to authorized users.

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“…The common targets include VEGFA and glucose transporter 1 (17). HIF-1 also induces the expression of glycolytic genes (18), some proangiogenic genes, and genes involved in pH regulation (19). HIF-2 stimulates matrix metalloproteinases and erythropoietin gene expression (20).…”

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Primary endothelial cell–specific regulation of hypoxia‐inducible factor (HIF)‐1 and HIF‐2 and their target gene expression profiles during hypoxia

et al. 2019

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During hypoxia, a cellular adaptive response activates hypoxia‐inducible factors (HIFs; HIF‐1 and HIF‐2) that respond to low tissue‐oxygen levels and induce the expression of a number of genes that promote angiogenesis, energy metabolism, and cell survival. HIF‐1 and HIF‐2 regulate endothelial cell (EC) adaptation by activating genesignaling cascades that promote endothelial migration, growth, and differentiation. An HIF‐1 to HIF‐2 transition or switch governs this process from acute to prolonged hypoxia. In the present study, we evaluated the mechanisms governing the HIF switch in 10 different primary human ECs from different vascular beds during the early stages of hypoxia. The studies demonstrate that the switch from HIF‐1 to HIF‐2 constitutes a universal mechanism of cellular adaptation to hypoxic stress and that HIF1A and HIF2A mRNA stability differences contribute to HIF switch. Furthermore, using 4 genome‐wide mRNA expression arrays of HUVECs during normoxia and after 2, 8, and 16 h of hypoxia, we show using bioinformatics analyses that, although a number of genes appeared to be regulated exclusively by HIF‐1 or HIF‐2, the largest number of genes appeared to be regulated by both.—Bartoszewski, R., Moszynska, A., Serocki, M., Cabaj, A., Polten, A., Ochocka, R., Dell'Italia, L., Bartoszewska, S., Króliczewski, J., Dabrowski, M., Collawn, J. F. Primary endothelial cell–specific regulation of hypoxia‐inducible factor (HIF)‐1 and HIF‐2 and their target gene expression profiles during hypoxia. FASEB J. 33, 7929–7941 (2019). http://www.fasebj.org

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Posttranscriptional and transcriptional regulation of endothelial nitric-oxide synthase during hypoxia: the role of microRNAs

Cited by 42 publications

References 104 publications

eNOS expression and NO release during hypoxia is inhibited by miR-200b in human endothelial cells

eNOS expression and NO release during hypoxia is inhibited by miR-200b in human endothelial cells

miRNAs regulate the HIF switch during hypoxia: a novel therapeutic target

Primary endothelial cell–specific regulation of hypoxia‐inducible factor (HIF)‐1 and HIF‐2 and their target gene expression profiles during hypoxia

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