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

Thounaojam, Menaka C.; Jadeja, Ravirajsinh N.; Warren, Marie; Powell, Folami Lamoke; Raju, Raghavan; Gutsaeva, Diana; Khurana, Sandeep; Martin, Pamela M.; Bartoli, Manuela

doi:10.3390/antiox8090328

Cited by 43 publications

(39 citation statements)

References 45 publications

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“…That study suggested oxidative/nitrative stress as a cause of premature senescence in diabetic retinas. Further investigation confirmed cellular senescence in human RECs subjected to HG which was associated with increased oxidative stress and mitochondrial dysfunction [94].…”

Section: Arginase In Premature Cellular Senescencementioning

confidence: 76%

Is the Arginase Pathway a Novel Therapeutic Avenue for Diabetic Retinopathy?

Shosha

Fouda

Narayanan

et al. 2020

JCM

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Diabetic retinopathy (DR) is the leading cause of blindness in working age Americans. Clinicians diagnose DR based on its characteristic vascular pathology, which is evident upon clinical exam. However, extensive research has shown that diabetes causes significant neurovascular dysfunction prior to the development of clinically apparent vascular damage. While laser photocoagulation and/or anti-vascular endothelial growth factor (VEGF) therapies are often effective for limiting the late-stage vascular pathology, we still do not have an effective treatment to limit the neurovascular dysfunction or promote repair during the early stages of DR. This review addresses the role of arginase as a mediator of retinal neurovascular injury and therapeutic target for early stage DR. Arginase is the ureohydrolase enzyme that catalyzes the production of L-ornithine and urea from L-arginine. Arginase upregulation has been associated with inflammation, oxidative stress, and peripheral vascular dysfunction in models of both types of diabetes. The arginase enzyme has been identified as a therapeutic target in cardiovascular disease and central nervous system disease including stroke and ischemic retinopathies. Here, we discuss and review the literature on arginase-induced retinal neurovascular dysfunction in models of DR. We also speculate on the therapeutic potential of arginase in DR and its related underlying mechanisms.

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Section: Arginase In Premature Cellular Senescencementioning

confidence: 76%

Is the Arginase Pathway a Novel Therapeutic Avenue for Diabetic Retinopathy?

Shosha

Fouda

Narayanan

et al. 2020

JCM

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“…Recent studies revealed that the microRNA might be an indispensable regulator (Yamakuchi and Hashiguchi, 2018). Thounaojam et al (2019) found that overexpression of miR-34a could decrease the expression of SIRT1 directly and induce mitochondrial dysfunction in high glucose-induced retinal endothelial cells. Thus, miR-155-5p, miR-106b, etc.…”

Section: Discussionmentioning

confidence: 99%

“…Furthermore, numerous microRNAs (miR-3197, miR-2116-5p, miR-152, miR-34a, etc. ) are identified as specificity biomarkers, and they participate directly in DR progression (Fu and Ou, 2019;Ji et al, 2019;Thounaojam et al, 2019). SIRT1 is a NAD + -dependent protein deacetylase, which plays important roles in metabolic regulation and adaptation (Boutant and Cantó, 2014).…”

Section: Introductionmentioning

confidence: 99%

MicroRNA-29b-3p Promotes Human Retinal Microvascular Endothelial Cell Apoptosis via Blocking SIRT1 in Diabetic Retinopathy

Yong

Cui²,

Liu³

et al. 2020

Front. Physiol.

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Background: Diabetic retinopathy (DR) is a main complication of diabetes mellitus (DM). Recent studies have implicated microRNAs in human retinal microvascular endothelial cell (HRMEC) dysfunction. In this study, we aim to investigate the apoptotic promotion of miR-29b-3p by blocking SIRT1 in HRMEC for DR situation. Method: Blood samples were obtained from DR patients and controls. Dual-luciferase reporter assay using HEK-293T cells was performed to show the direct interaction of miR-29b-3p and the 3 UTR of SIRT1. HRMECs were exposed to 5.5 mmol/L of glucose (normal control), 5.5 mmol/L of glucose and 24.5 mmol/L of mannitol (osmotic pressure control), 30 mmol/L of glucose [hyperglycemia (HG)], 150 µmol/L of CoCl 2 (hypoxia), and 30 mmol/L of glucose plus 150 µmol/L of CoCl 2 (HG-CoCl 2). To identify the regulating relationship between miR-29b-3p and SIRT1, HRMECs were transfected with miR-29b-3p mimics/inhibitors or their negative controls. SRT1720 was used as a SIRT1 agonist. Cell viability was assessed with the cell counting kit-8 (CCK-8) assay, and apoptotic cells were stained by one-step terminal deoxynucleotidyl transferase dUTP nick end labeling (TUNEL) assay kit. Gene and protein expression were assayed by quantitative real-time reverse transcriptase-PCR (RT-qPCR) and western blotting separately. Result: MiR-29b-3p was upregulated to 3.2-fold, and SIRT1 protein was downregulated to 65% in DR patients. Dual-luciferase reporter assay showed the direct interaction of miR-29b-3p and SIRT1. HRMECs were identified as >95% positive for CD31 and von Willebrand factor (vWF). MiR-29b-3p and Bax/Bcl-2 ratio was upregulated, whereas SIRT1 was downregulated in HRMECs in the HG-CoCl 2 condition. Decreased cell viability and upregulated apoptosis were also found in HRMECs of the HG-CoCl 2 condition. Upregulated miR-29b-3p decreased the expression of SIRT1 and increased the ratio of Bax/Bcl-2, whereas downregulated miR-29b-3p increased the expression of SIRT1 protein and downregulated the ratio of

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“…Accordingly, caloric restriction presented cardioprotective effects through SIRT1/PGC-1α activation in ob/ob mice with cardiac hypertrophy [195]. Finally, a recent study into human retinal microvascular endothelial cells has demonstrated that high glucose stimulation increases miR-34a expression, which induces cellular senescence by mitochondrial dysfunction and loss of antioxidant capacity through PGC-1α deficiency [196].…”

Section: Type 2 Diabetesmentioning

confidence: 99%

PGC-1α, Inflammation, and Oxidative Stress: An Integrative View in Metabolism

Rius‐Pérez

Torres-Cuevas

Millán

et al. 2020

Oxidative Medicine and Cellular Longevity

403

292

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Peroxisome proliferator-activated receptor-γ coactivator (PGC)-1α is a transcriptional coactivator described as a master regulator of mitochondrial biogenesis and function, including oxidative phosphorylation and reactive oxygen species detoxification. PGC-1α is highly expressed in tissues with high energy demands, and it is clearly associated with the pathogenesis of metabolic syndrome and its principal complications including obesity, type 2 diabetes mellitus, cardiovascular disease, and hepatic steatosis. We herein review the molecular pathways regulated by PGC-1α, which connect oxidative stress and mitochondrial metabolism with inflammatory response and metabolic syndrome. PGC-1α regulates the expression of mitochondrial antioxidant genes, including manganese superoxide dismutase, catalase, peroxiredoxin 3 and 5, uncoupling protein 2, thioredoxin 2, and thioredoxin reductase and thus prevents oxidative injury and mitochondrial dysfunction. Dysregulation of PGC-1α alters redox homeostasis in cells and exacerbates inflammatory response, which is commonly accompanied by metabolic disturbances. During inflammation, low levels of PGC-1α downregulate mitochondrial antioxidant gene expression, induce oxidative stress, and promote nuclear factor kappa B activation. In metabolic syndrome, which is characterized by a chronic low grade of inflammation, PGC-1α dysregulation modifies the metabolic properties of tissues by altering mitochondrial function and promoting reactive oxygen species accumulation. In conclusion, PGC-1α acts as an essential node connecting metabolic regulation, redox control, and inflammatory pathways, and it is an interesting therapeutic target that may have significant benefits for a number of metabolic diseases.

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

Cited by 43 publications

References 45 publications

Is the Arginase Pathway a Novel Therapeutic Avenue for Diabetic Retinopathy?

Is the Arginase Pathway a Novel Therapeutic Avenue for Diabetic Retinopathy?

MicroRNA-29b-3p Promotes Human Retinal Microvascular Endothelial Cell Apoptosis via Blocking SIRT1 in Diabetic Retinopathy

PGC-1α, Inflammation, and Oxidative Stress: An Integrative View in Metabolism

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