miR-146a is modulated in human endothelial cell with aging (original) (raw)
Related papers
MicroRNA 299-3p modulates replicative senescence in endothelial cells
Physiological genomics, 2013
MicroRNAs (miRNAs) regulate various cellular processes. While several genes associated with replicative senescence have been described in endothelial cells, miRNAs that regulate these genes remain largely unknown. The present study was designed to identify miRNAs associated with replicative senescence and their target genes in human umbilical vein endothelial cells (HUVECs). An integrated miRNA and gene profiling approach revealed that hsa-miR-299-3p is upregulated in senescent HUVECs compared with the young cells, and one of its target genes could be IGF1. IGF1 was upregulated in senescent compared with young HUVECs, and knockdown of hsa-miR-299-3p dose-dependently increased the mRNA expression of IGF1, more significantly observed in the presenescent cells (passage 19) compared with the senescent cells (passage 25). Knockdown of hsa-miR-299-3p also resulted in significant reduction in the percentage of cells positively stained for senescence-associated β-galactosidase and increases...
Quantitative and integrated proteome and microRNA analysis of endothelial replicative senescence
Journal of Proteomics, 2015
Age-related changes in vascular functioning are a harbinger of cardiovascular disease but the biological mechanisms during the progression of endothelial senescence have not been studied. We investigated alterations in the proteome and miRNA profiles in the course of replicative senescence using primary human umbilical vein endothelial cells as an in vitro vascular model. Quantitative proteomic profiling from early growth stage to senescence was performed by isotope-coded protein label coupled to LC-ESI-MS/MS analysis. Some proteins consistently changed their expression during the senescence whereas others appeared as deregulated only during the late senescence. The latter was accompanied by alterations in morphology of senescent endothelial cells. MicroRNA expression profiling revealed transient changes in the level of miR-16-5p, miR-28-3p and miR-886-5p in the early senescence, decrease in the level of miR-106b-3p at the late stage, and continuous changes in the expression of miR-181a-5p and miR-376a-3p during the whole senescence process. Integrating data on proteomic and microRNA changes indicated potential crosstalk between specific proteins and non-coding RNAs in the regulation of metabolism, cell cycle progression and cytoskeletal organization in the endothelial senescence. The knowledge of molecular targets that change during the senescence can ultimately contribute to a better understanding and prevention of age-related vascular diseases.
MicroRNAs orchestrating senescence of endothelial and vascular smooth muscle cells
Vascular Biology, 2019
During organism aging, the process of cellular senescence is triggered by critical stressors such as DNA damage, oncogenes, oxidative stress, and telomere erosion, and vascular cells are not exempted. Senescent cells stop proliferating but remain metabolically active producing pro-inflammatory signals in the environment collectively named senescence-associated secretory phenotype (SASP) that contribute to the amplification of the response to the neighbor and distant cells. Although the shift toward senescence is protective against tumors and needed during wound healing, the accumulation of senescent cells during aging due to an impairment of the immune system deputed to their clearance, can predispose to diseases of the cardiovascular system such as atherosclerosis. In this short review, we describe the main features of senescence of endothelial and smooth muscle cells and focus on the role non-coding RNAs of the microRNAs class in controlling this process. Finally, we discuss the p...
Vascular ageing and endothelial cell senescence: Molecular mechanisms of physiology and diseases
Mechanisms of ageing and development, 2016
Ageing leads to a progressive deterioration of structure and function of all organs over the time. During this process endothelial cells undergo senescence and manifest significant changes in their properties, resulting in impairment of the vascular functionality and neo-angiogenic capability. This ageing-dependent impairment of endothelial functions is considered a key factor contributing to vascular dysfunctions, which is responsible of several age-related diseases of the vascular system and other organs. Several mechanisms have been described to control ageing-related endothelial cell senescence including microRNAs, mitochondrial dysfunction and micro environmental stressors, such as hypoxia. In this review, we attempt to summarize the recent literature in the field, discussing the major mechanisms involved in endothelial cell senescence. We also underline key molecular aspects of ageing-associated vascular dysfunction in the attempt to highlight potential innovative therapeutic ...
Experimental reduction of miR-92a mimics arterial aging
Experimental Gerontology, 2016
MicroRNAs (miRs) are small non-coding RNAs that are important regulators of aging and cardiovascular diseases. MiR-92a is important in developmental vascular growth and tumorigenesis and two of its putative targets, tumor necrosis factor alpha receptor (TNFR1) and collagen type1, play a role in age-related arterial dysfunction. We hypothesized that reduced miR-92a expression contributes to age-related arterial dysfunction characterized by endothelial dysfunction and increased large artery stiffness. MiR-92a is reduced 39% (p<0.05, RT-PCR) in arteries of older adults compared to young adults. Similarly, there was a 40% reduction in miR-92a in aortas of old (29 mo, n=13) compared to young (6 mo, n=11) B6D2F1 mice, an established model of vascular aging. To determine if reduced miR-92a contributes to arterial dysfunction; miR-92a was inhibited in vivo in young mice using antagomirs (I.P., 4 weeks). Antagomir treatment was associated with a concomitant 48% increase in TNFR1 (Western blot, p<0.05), 19% increase in type 1 collagen (immunohistochemistry, p<0.01), and a reduction in endothelial dependent dilation (max dilation: 93±1 v 73±5 %, p<0.01) in response to acetylcholine (ACh, 10 −9 to 10 −4 M). Treatment with the nitric oxide (NO) synthase inhibitor, L-NAME (10 −4 M), revealed that impaired ACh dilation after antagomir treatment resulted from reduced NO bioavailability. Inhibition of miR-92a also increased arterial stiffness (309±13 vs. 484±52 cm/s, p<0.05, pulse wave velocity). Together, these results suggest that experimental reductions in arterial miR-92a partially mimic the arterial aging phenotype and we speculate that modulating miR-92a may provide a therapeutic strategy to improve age-related arterial dysfunction.
MicroRNA 217 Modulates Endothelial Cell Senescence via Silent Information Regulator 1
Circulation, 2009
Background-Aging is a major risk factor for the development of atherosclerosis and coronary artery disease. Through a microarray approach, we have identified a microRNA (miR-217) that is progressively expressed in endothelial cells with aging. miR-217 regulates the expression of silent information regulator 1 (SirT1), a major regulator of longevity and metabolic disorders that is progressively reduced in multiple tissues during aging. Methods and Results-miR-217 inhibits SirT1 expression through a miR-217-binding site within the 3Ј-UTR of SirT1. In young human umbilical vein endothelial cells, human aortic endothelial cells, and human coronary artery endothelial cells, miR-217 induces a premature senescence-like phenotype and leads to an impairment in angiogenesis via inhibition of SirT1 and modulation of FoxO1 (forkhead box O1) and endothelial nitric oxide synthase acetylation. Conversely, inhibition of miR-217 in old endothelial cells ultimately reduces senescence and increases angiogenic activity via an increase in SirT1. miR-217 is expressed in human atherosclerotic lesions and is negatively correlated with SirT1 expression and with FoxO1 acetylation status. Conclusions-Our data pinpoint miR-217 as an endogenous inhibitor of SirT1, which promotes endothelial senescence and is potentially amenable to therapeutic manipulation for prevention of endothelial dysfunction in metabolic disorders. (Circulation. 2009;120:1524-1532.)
Role of microRNAs in endothelial cell pathophysiology
Polskie Archiwum Medycyny Wewnętrznej, 2011
MicroRNAs (miRNAs) are a family of small, noncoding RNAs that repress gene expression at the post-transcriptional level. Over 700 miRNAs have been identified in the human genome, of which 20% to 30% regulate human protein-coding genes. Functional in vitro studies have shown that miRNAs are critical for endothelial cell gene expression and function. miRNAs were found in atherosclerosis, cardiac hypertrophy, arterial hypertension, coronary artery disease, diabetes, and inflammatory diseases. We review the current knowledge about the role of miRNAs in endothelial cells with emphasis on the regulation of cellular senescence, angiogenesis, and vascular inflammation. It has been shown that miR-34a, miR-217, miR-200, miR-146c, and miR-181a are responsible for the regulation of cell stress and proliferation processes. Proangiogenic factors include miR-130a, miR-210, miR-424, miR-17-92, miR-27-b, let-7f, and miR-217, while miR-221 and miR-222 have antiangiogenic properties. Other known miRNA...
Aging-Associated miR-217 Aggravates Atherosclerosis and Promotes Cardiovascular Dysfunction
Arteriosclerosis, Thrombosis, and Vascular Biology, 2020
Objective: microRNAs are master regulators of gene expression with essential roles in virtually all biological processes. miR-217 has been associated with aging and cellular senescence, but its role in vascular disease is not understood. Approach and Results: We have used an inducible endothelium-specific knock-in mouse model to address the role of miR-217 in vascular function and atherosclerosis. miR-217 reduced NO production and promoted endothelial dysfunction, increased blood pressure, and exacerbated atherosclerosis in proatherogenic apoE −/ − mice. Moreover, increased endothelial miR-217 expression led to the development of coronary artery disease and altered left ventricular heart function, inducing diastolic and systolic dysfunction. Conversely, inhibition of endogenous vascular miR-217 in apoE −/− mice improved vascular contractility and diminished atherosclerosis. Transcriptome analysis revealed that miR-217 regulates an endothelial signaling hub and downregulates a networ...
Scientific Reports
Whereas a healthy endothelium maintains physiological vascular functions, endothelial damage contributes to the development of cardiovascular diseases. Endothelial senescence is the main determinant of endothelial dysfunction and thus of age-related cardiovascular disease. The objective of this study is to test the involvement of microRNA-126 and HIF-1α in a model of replicative endothelial senescence and the interrelationship between both molecules in this in vitro model. We demonstrated that senescent endothelial cells experience impaired tube formation and delayed wound healing. Senescent endothelial cells failed to express HIF-1α, and the microvesicles released by these cells failed to carry HIF-1α. Of note, HIF-1α protein levels were restored in HIF-1α stabilizer-treated senescent endothelial cells. Finally, we show that microRNA-126 was downregulated in senescent endothelial cells and microvesicles. With regard to the interplay between microRNA-126 and HIF-1α, transfection with a microRNA-126 inhibitor downregulated HIF-1α expression in early passage endothelial cells. Moreover, while HIF-1α inhibition reduced tube formation and wound healing closure, microRNA-126 levels remained unchanged. These data indicate that HIF-1α is a target of miRNA-126 in protective and reparative functions, and suggest that their therapeutic modulation could benefit age-related vascular disease.
miR17, miR19b, miR20a, and miR106a are down-regulated in human aging
Aging Cell, 2010
Aging is a multifactorial process where deterioration of body functions is driven by stochastic damage while counteracted by distinct genetically encoded repair systems. To better understand the genetic component of aging, many studies have addressed the gene and protein expression profiles of various aging model systems engaging different organisms from yeast to human. The recently identified small non-coding miRNAs are potent post-transcriptional regulators that can modify the expression of up to several hundred target genes per single miRNA, similar to transcription factors. Increasing evidence shows that miRNAs contribute to the regulation of most if not all important physiological processes, including aging. However, so far the contribution of miRNAs to age-related and senescence-related changes in gene expression remains elusive. To address this question, we have selected four replicative cell aging models including endothelial cells, replicated CD8 + T cells, renal proximal tubular epithelial cells, and skin fibroblasts. Further included were three organismal aging models including foreskin, mesenchymal stem cells, and CD8 + T cell populations from old and young donors. Using locked nucleic acid-based miRNA microarrays, we identified four commonly regulated miRNAs, miR-17 down-regulated in all seven; miR-19b and miR-20a, down-regulated in six models; and miR-106a down-regulated in five models. Decrease in these miRNAs correlated with increased transcript levels of some established target genes, especially the cdk inhibitor p21 ⁄ CDKN1A. These results establish miRNAs as novel markers of cell aging in humans.