Disturbed Flow Increases UBE2C (Ubiquitin E2 Ligase C) via Loss of miR-483-3p, Inducing Aortic Valve Calcification by the pVHL (von Hippel-Lindau Protein) and HIF-1α (Hypoxia-Inducible Factor-1α) Pathway in Endothelial Cells

Esmerats, Joan Fernández; Villa-Roel, Nicolas; Kumar, Sandeep; Gu, Lina; Salim, Tausif; Ohh, Michael; Taylor, W. Robert; Nerem, Robert M.; Yoganathan, Ajit P.; Jo, Hanjoong

doi:10.1161/atvbaha.118.312233

Cited by 62 publications

(49 citation statements)

References 72 publications

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“…These studies revealed that HIF-1α can be activated by disturbed blood flow in vivo. In addition, these studies, using in vitro flow systems that recapitulate the shear stress in vivo, show that endothelial cells exposed to disturbed flow under normoxic conditions had elevated HIF-1α mRNA and protein levels [9,11,96]. Thus, it appears from these findings that both hypoxia induced by disturbed flow, and disturbed flow itself can induce HIF-1α expression.…”

Section: Disturbed Flow Activates Hif-1αmentioning

confidence: 86%

“…Consistent with this, Feng et al [9] show that HIF-1α was also elevated at sites of disturbed flow in porcine and murine arteries. A study by Fernandez Esmerats et al [96] shows that HIF-1α was enhanced in endothelial cells exposed to disturbed flow located at the fibrosa Figure 4. Outline of simplified mass transport considerations for oxygen transport to a blood vessel wall.…”

Section: Disturbed Flow Activates Hif-1αmentioning

confidence: 99%

“…Fernandez Esmerats et al show that downregulation of miR483 by disturbed flow leads to elevated HIF-1α levels in endothelial cells through enhanced expression of a miR483-target gene UBE2C, which functions as an ubiquitinating protein that degrades VHL, leading to HIF-1α accumulation. Elevated HIF-1α levels promote inflammation and endothelial-mesenchymal transition in endothelial cells, leading to dysfunction and calcification in the aortic valve [96].…”

Section: Disturbed Flow Activates Hif-1αmentioning

confidence: 99%

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The role of oxygen transport in atherosclerosis and vascular disease

Tarbell

Mahmoud

Corti

et al. 2020

J. R. Soc. Interface.

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Atherosclerosis and vascular disease of larger arteries are often associated with hypoxia within the layers of the vascular wall. In this review, we begin with a brief overview of the molecular changes in vascular cells associated with hypoxia and then emphasize the transport mechanisms that bring oxygen to cells within the vascular wall. We focus on fluid mechanical factors that control oxygen transport from lumenal blood flow to the intima and inner media layers of the artery, and solid mechanical factors that influence oxygen transport to the adventitia and outer media via the wall's microvascular system—the vasa vasorum (VV). Many cardiovascular risk factors are associated with VV compression that reduces VV perfusion and oxygenation. Dysfunctional VV neovascularization in response to hypoxia contributes to plaque inflammation and growth. Disturbed blood flow in vascular bifurcations and curvatures leads to reduced oxygen transport from blood to the inner layers of the wall and contributes to the development of atherosclerotic plaques in these regions. Recent studies have shown that hypoxia-inducible factor-1α (HIF-1α), a critical transcription factor associated with hypoxia, is also activated in disturbed flow by a mechanism that is independent of hypoxia. A final section of the review emphasizes hypoxia in vascular stenting that is used to enlarge vessels occluded by plaques. Stenting can compress the VV leading to hypoxia and associated intimal hyperplasia. To enhance oxygen transport during stenting, new stent designs with helical centrelines have been developed to increase blood phase oxygen transport rates and reduce intimal hyperplasia. Further study of the mechanisms controlling hypoxia in the artery wall may contribute to the development of therapeutic strategies for vascular diseases.

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Section: Disturbed Flow Activates Hif-1αmentioning

confidence: 86%

Section: Disturbed Flow Activates Hif-1αmentioning

confidence: 99%

Section: Disturbed Flow Activates Hif-1αmentioning

confidence: 99%

See 1 more Smart Citation

The role of oxygen transport in atherosclerosis and vascular disease

Tarbell

Mahmoud

Corti

et al. 2020

J. R. Soc. Interface.

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“…Further, more than one hundred genes have been identified to be governed by mammalian HIF during O 2 deprivation [42,43]. The involvement of HIF-1α in diseases of the vascular wall, including atherosclerosis, carotid stenosis, and aneurysms, has recently been proposed [44][45][46][47][48][49]. Indeed, insufficient expression of HIF is associated with CVD [50,51].…”

Section: Hypoxia-inducible Factorsmentioning

confidence: 99%

Hypoxia-Inducible Factor-1α: The Master Regulator of Endothelial Cell Senescence in Vascular Aging

Alique

Sánchez-López

Bodega

et al. 2020

Cells

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Aging is one of the hottest topics in biomedical research. Advances in research and medicine have helped to preserve human health, leading to an extension of life expectancy. However, the extension of life is an irreversible process that is accompanied by the development of aging-related conditions such as weakness, slower metabolism, and stiffness of vessels. It also debated that aging can be considered an actual disease with aging-derived comorbidities, including cancer or cardiovascular disease. Currently, cardiovascular disorders, including atherosclerosis, are considered as premature aging and represent the first causes of death in developed countries, accounting for 31% of annual deaths globally. Emerging evidence has identified hypoxia-inducible factor-1α as a critical transcription factor with an essential role in aging-related pathology, in particular, regulating cellular senescence associated with cardiovascular aging. In this review, we will focus on the regulation of senescence mediated by hypoxia-inducible factor-1α in age-related pathologies, with particular emphasis on the crosstalk between endothelial and vascular cells in age-associated atherosclerotic lesions. More specifically, we will focus on the characteristics and mechanisms by which cells within the vascular wall, including endothelial and vascular cells, achieve a senescent phenotype.

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“…The expression of CDCA5 was reported to be closely linked to microvascular invasion and tumor diameter, and inhibition of CDCA5 expression impeded hepatoma cell proliferation and induced apoptosis (37). UBE2C was indicated to be highly expressed in HCC tumor tissues and patients with upregulated UBE2C were more likely to have higher-grade tumors and poor prognosis (38,39). Overexpression of MELK leads to cell cycle-and mitosis-associated gene expression, which influences cell division.…”

Section: Discussionmentioning

confidence: 99%

CCNB2, NUSAP1 and TK1 are associated with the prognosis and progression of hepatocellular carcinoma, as revealed by co‑expression analysis

Liu

Chen

et al. 2020

Exp Ther Med

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The mortality rate associated with hepatocellular carcinoma (HCC) is the third highest among all digestive system tumors. However, the causes of HCC development and the underlying mechanisms have remained to be fully elucidated. In the present bioinformatics study, genetic markers were identified and their association with HCC was determined. The mRNA expression datasets GSE87630, GSE74656 and GSE76427 were downloaded from the Gene Expression Omnibus (GEO) database. A total of 96 differentially expressed genes (DEGs) were screened from the 3 GEO datasets, including 25 upregulated and 71 downregulated genes. DEGs were uploaded to the database for Annotation, Visualization and Integrated Discovery to screen for enriched Gene Ontology terms in various categories and the Search Tool for the Retrieval of Interacting Genes/Proteins was used to identify the interactions and functions of the DEGs. A total of 3 genetic markers were identified in a stepwise pathway and functional analysis in a previous study. The association of the genetic markers with prognosis was analysed using the UALCAN online analysis tool. Regression analysis was also performed to identify the relationship between HCC grade and disease recurrence and the expression of genetic markers using The Cancer Genome Atlas HCC dataset. In addition, the expression of the 3 genetic markers in HCC tissues was determined using reverse transcription-quantitative PCR, the Oncomine database and the Human Protein Atlas database. The expression levels of the 3 genetic markers cyclin B2 (CCNB2), nucleolar and spindle-associated protein 1 (NUSAP1) and thymidine kinase 1 (TK1) were significantly correlated with each other and high mRNA expression of CCNB2 was significantly associated with poor overall survival of patients with HCC. Receiver operating characteristic curve analysis indicated that NUSAP1 and TK1 were capable of distinguishing between recurrent and non-recurrent HCC. Furthermore, CCNB2, NUSAP1 and TK1 were highly correlated with the HCC grade. It was also indicated that the mRNA expression of CCNB2, NUSAPA and TK1 was increased in primary HCC tissues when compared with that in adjacent tissues. The present study identified that the CCNB2, NUSAP1 and TK1 genes may serve as prognostic markers for HCC, and may be of value from the perspectives of basic research and clinical treatment of HCC.

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Disturbed Flow Increases UBE2C (Ubiquitin E2 Ligase C) via Loss of miR-483-3p, Inducing Aortic Valve Calcification by the pVHL (von Hippel-Lindau Protein) and HIF-1α (Hypoxia-Inducible Factor-1α) Pathway in Endothelial Cells

Cited by 62 publications

References 72 publications

The role of oxygen transport in atherosclerosis and vascular disease

The role of oxygen transport in atherosclerosis and vascular disease

Hypoxia-Inducible Factor-1α: The Master Regulator of Endothelial Cell Senescence in Vascular Aging

CCNB2, NUSAP1 and TK1 are associated with the prognosis and progression of hepatocellular carcinoma, as revealed by co‑expression analysis

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