Intravenous Injection of miR-34a Inhibitor Alleviates Diabetes Mellitus-Induced Vascular Endothelial Dysfunction by Targeting NOTCH1

Zhao, Di; Wang, Na-Sui; Fu, Chen; Li, Zheng-Bing; Li, Xitao; Zhu, Xuxin

doi:10.1055/s-0043-125324

Cited by 11 publications

(6 citation statements)

References 38 publications

(46 reference statements)

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“…In the present study miRNA- proliferative DR, supporting that miRNA-21 may play a role in DR (52) In addition, diabetes-was reported to induce PPAR-α downregulation has been shown to play a key role in retinal inflammation in DR (53) . These data can be supported by previous studies indicated increased expression of miRNA-34a in experimental and human diabetes, which in turn is linked to hyperglycemia-induced vascular dysfunction (54) , oxidative stress (55) , and apoptosis. Thounaojam et al (56) explained that increased oxidative/nitrative stress plays a causal role in retinal vascular dysfunction and hyperglycemia-induced premature senescence (57) .…”

Section: Eye Examinationsupporting

confidence: 82%

Possible Correlation between Severity of Retinopathy and Blood Levels of miRNAs (-146, -21 and 34a) in Type 2 Diabetic Patients.

Helal

Abdullah

Salem

et al. 2020

Benha Medical Journal

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Background: Diabetic Retinopathy (DR), a leading cause of acquired visual loss, is a microvascular complication of DM, among the middle-aged and economically active population. At present, there is a lack of accuracy and specificity in our ability to identify this particular cohort. As the disease remains asymptomatic until the pathology is significantly advanced, screening to detect it during the early stages is necessary. Ability of miRNAs to alter or fine tune the expression of key regulators in various physiological processes and pathophysiological disease states makes them novel targets for diseases such as diabetic complications. Aim: The present work aimed to find out the possibility to use the expression pattern of miRNAs (146a, 21, and 34a) as biomarkers for early detection of DR in addition to the underling mechanisms. Also, to evaluate the correlation between them in each stage of DR to help in diagnosis by simple noninvasive methods. Patients and methods: Eighty patients with type 2 diabetes mellitus were involved in this study and diagnosed after investigation into normal, mild, moderate, severe NPDR and PDR patients. miRNAs 1436a,-21 and 34a were evaluated in the serum of patients in each group. Results: The present study revealed that the levels of miRNA-146 and miRNA-21 are increased in serum of DR patients in direct relation with the severity. However, serum miRNA-34a is decreased with progression of the disease. Conclusion miRNAs level in the serum of diabetic patients can be used as diagnostic biomarkers of DR.

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Section: Eye Examinationsupporting

confidence: 82%

Possible Correlation between Severity of Retinopathy and Blood Levels of miRNAs (-146, -21 and 34a) in Type 2 Diabetic Patients.

Helal

Abdullah

Salem

et al. 2020

Benha Medical Journal

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“…The contribution of miR-34a to vascular senescence and apoptosis has been previously documented [12,14,15,18], and increased expression of this miR has been found in human and experimental diabetes [22,23,24]. Our group and others have previously shown that miR-34a levels are increased in retinas of diabetic rats [3,36] and this effect is associated with retinal vascular senescence and loss of expression and activity of SIRT1, a validated target of this miR [12,37].…”

Section: Discussionmentioning

confidence: 99%

“…Altered expression of miR-34a is evident in several human pathologies, including cancer [18,19] and cardiovascular disease [20,21]. Both, experimental and human diabetes are associated with increased expression of miR-34a, which in turn is linked to hyperglycemia-induced vascular dysfunction [22,23,24]. Previously we have showed that miR-34a is upregulated in the diabetic retina [3] and this effect is associated with increased levels of senescence markers and loss of SIRT1 expression and activity [3].…”

Section: Introductionmentioning

confidence: 99%

MicroRNA-34a (miR-34a) Mediates Retinal Endothelial Cell Premature Senescence through Mitochondrial Dysfunction and Loss of Antioxidant Activities

et al. 2019

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Stress-associated premature senescence (SAPS) is involved in retinal microvascular injury and diabetic retinopathy. We have investigated the role and mode of action of miR-34a in retinal endothelial cells senescence in response to glucidic stress. Human retinal microvascular endothelial cells (HuREC) were exposed to glucidic stress (high glucose (HG) = 25 mM d-glucose) and compared to cells exposed to normal glucose (NG = 5 mM) or the osmotic control l-glucose (LG = 25 mM). HG stimulation of HuREC increased the expression of miR-34a and induced cellular senescence. HG also increased the expression of p16ink4a and p21waf1, while decreasing the histone deacetylase SIRT1. These effects were associated with diminished mitochondrial function and loss of mitochondrial biogenesis factors (i.e., PGC-1α, NRF1, and TFAM). Transfection of the cells with miR-34a inhibitor (IB) halted HG-induced mitochondrial dysfunction and up-regulation of senescence-associated markers, whereas miR-34a mimic promoted cellular senescence and mitochondrial dysfunction. Moreover, HG lowered levels of the mitochondrial antioxidants TrxR2 and SOD2, an effect blunted by miR-34a IB, and promoted by miR-34a mimic. 3’-UTR (3’-untranslated region) reporter assay of both genes validated TrxR2 as a direct target of miR-34a, but not SOD2. Our results show that miR-34a is a key player of HG-induced SAPS in retinal endothelial cells via multiple pathways involved in mitochondrial function and biogenesis.

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“…16 MiR-34a was reported to target Notch mRNA and exacerbate diabetic endothelial dysfunction 41 in rats. 16 MiR-34a was reported to target Notch mRNA and exacerbate diabetic endothelial dysfunction 41 in rats.…”

Section: Discussionmentioning

confidence: 99%

“…MiR-34a targets multiple mRNAs. 16 MiR-34a was reported to target Notch mRNA and exacerbate diabetic endothelial dysfunction 41 in rats. In the present study, SIRT1 was found to indicating a potential SIRT1/NOTCH pathway in protecting against diabetic endothelial dysfunction.…”

Section: Discussionmentioning

confidence: 99%

Inhibition of P53/miR‐34a improves diabetic endothelial dysfunction via activation of SIRT1

Wang

Tian

et al. 2019

J Cellular Molecular Medi

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Endothelial dysfunction contributes to diabetic macrovascular complications, resulting in high mortality. Recent findings demonstrate a pathogenic role of P53 in endothelial dysfunction, encouraging the investigation of the effect of P53 inhibition on diabetic endothelial dysfunction. Thus, high glucose (HG)‐treated endothelial cells (ECs) were subjected to pifithrin‐α (PFT‐α)—a specific inhibitor of P53, or P53 ‐small interfering RNA (siRNA), both of which attenuated the HG‐induced endothelial inflammation and oxidative stress. Moreover, inhibition of P53 by PFT‐α or P53 ‐siRNA prohibited P53 acetylation, decreased microRNA‐34a (miR‐34a) level, leading to a dramatic increase in sirtuin 1 (SIRT1) protein level. Interestingly, the miR‐34a inhibitor (miR‐34a‐I) and PFT‐α increased SIRT1 protein level and alleviated the HG‐induced endothelial inflammation and oxidative stress to a similar extent; however, these effects of PFT‐α were completely abrogated by the miR‐34a mimic. In addition, SIRT1 inhibition by EX‐527 or Sirt1 ‐siRNA completely abolished miR‐34a‐I's protection against HG‐induced endothelial inflammation and oxidative stress. Furthermore, in the aortas of streptozotocin‐induced diabetic mice, both PFT‐α and miR‐34a‐I rescued the inflammation, oxidative stress and endothelial dysfunction caused by hyperglycaemia. Hence, the present study has uncovered a P53/miR‐34a/SIRT1 pathway that leads to endothelial dysfunction, suggesting that P53/miR‐34a inhibition could be a viable strategy in the management of diabetic macrovascular diseases.

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Intravenous Injection of miR-34a Inhibitor Alleviates Diabetes Mellitus-Induced Vascular Endothelial Dysfunction by Targeting NOTCH1

Abstract: These results provide evidence to support the use of miR-34a inhibitors as a therapeutic approach attenuating hyperglycemia-induced vascular endothelial dysfunction.

Cited by 11 publications

References 38 publications

Possible Correlation between Severity of Retinopathy and Blood Levels of miRNAs (-146, -21 and 34a) in Type 2 Diabetic Patients.

Possible Correlation between Severity of Retinopathy and Blood Levels of miRNAs (-146, -21 and 34a) in Type 2 Diabetic Patients.

MicroRNA-34a (miR-34a) Mediates Retinal Endothelial Cell Premature Senescence through Mitochondrial Dysfunction and Loss of Antioxidant Activities

Inhibition of P53/miR‐34a improves diabetic endothelial dysfunction via activation of SIRT1

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