MicroRNA-146a Decreases High Glucose/Thrombin-Induced Endothelial Inflammation by Inhibiting NAPDH Oxidase 4 Expression

Wang, Huang-Joe; Huang, Yuan‐Li; Shih, Ya-Yun; Wu, Heng-Hsiung; Peng, Ching‐Tien; Lo, Wan-Yu

doi:10.1155/2014/379537

Cited by 77 publications

(77 citation statements)

References 52 publications

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“…However, the function of miR-146a-5p is poorly understood in endothelial cells treated by transient high glucose. In this study, we found that high glucose could decrease the expression of miR-146a-5p in HAECs, as previously reported (26). Furthermore, this decrease of miR-146a-5p persisted even the HAECs was not in the condition of the previous high glucose.…”

Section: Discussionsupporting

confidence: 91%

“…Villeneuve et al provided miR125b increased in the vascular smooth muscle cells of diabetic db/db mice (25); our data showed that miR-125b also increased in HAECs treated with transient or persistent high glucose. Wang et al identified treatment with high glucose significantly decreased miR-146a expression in HAECs, as our reported (26). NF-B is a transcription factor which is able to further stimulate expression of many inflammatory genes (27), and has turned out to play an important role in the pathogenesis of atherosclerosis (28,29).…”

Section: Discussionsupporting

confidence: 73%

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The MicroRNAs in the Pathogenesis of Metabolic Memory

et al. 2015

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"Metabolic memory" is identified as a phenomenon that previous exposure to hyperglycemia results in the long-lasting deleterious effects on cardiovascular events. More and more researches show that epigenetics plays an important role in the pathogenesis of metabolic memory. It remains unclear whether microRNA (miRNA) dysfunctions participate in the event. In this study, the miRNA arrays on human aortic endothelial cells were adopted to seek the miRNAs that may be involved in the metabolic memory and were verified in vivo and in vitro. Sixteen miRNAs were found differentially expressed. Among these miRNAs, the expressions of miR-125b, miR-146a-5p, and miR-29a-3p were associated with persistent impaired endothelial function and altered proinflammatory gene expressions, including nuclear factor-κB (NF-κB) subunit p65. Direct inhibition of miR-125b expression or increased miR-146a-5p expression blunted NF-κB signals and improved the endothelial function. Luciferase reporter assays confirmed the biochemical relationship for miR-125b targeting on TNF-α-induced protein 3 and miR-146a-5p targeting on TNF receptor-associated factor 6 and IL-1 receptor-associated kinase 1 during the activation of NF-κB pathway. Thus, our findings demonstrate that glucose induced changes in miR-125b and miR-146a-5p are related to the long-lasting activation of NF-κB pathway and contribute to follow-up metabolic memory.

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Section: Discussionsupporting

confidence: 91%

Section: Discussionsupporting

confidence: 73%

The MicroRNAs in the Pathogenesis of Metabolic Memory

et al. 2015

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“…Expression of immune-modulatory miRNAs, especially miR-146a, has been determined in different diabetic complications, [48][49][50][51][52] including DN. 49,[53][54][55] While some studies have shown lower miR-146a expression during DN, 49 others have shown higher expression.…”

Section: Discussionmentioning

confidence: 99%

Anti-Inflammatory Role of MicroRNA-146a in the Pathogenesis of Diabetic Nephropathy

Bhatt

Lanting

Jia

et al. 2015

JASN

159

130

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Inflammation has a critical role in the pathogenesis of diabetic complications, including diabetic nephropathy (DN). MicroRNAs have recently emerged as important regulators of DN. However, the role of microRNAs in the regulation of inflammation during DN is poorly understood. Here, we examined the in vivo role of microRNA-146a (miR-146a), a known anti-inflammatory microRNA, in the pathogenesis of DN. In a model of streptozotocin-induced diabetes, miR-146a 2/2 mice showed significantly exacerbated proteinuria, renal macrophage infiltration, glomerular hypertrophy, and fibrosis relative to the respective levels in control wild-type mice. Diabetes-induced upregulation of proinflammatory and profibrotic genes was significantly greater in the kidneys of miR-146a 2/2 than in the kidneys of wild-type mice. Notably, miR146a expression increased in both peritoneal and intrarenal macrophages in diabetic wild-type mice. Mechanistically, miR-146a deficiency during diabetes led to increased expression of M1 activation markers and suppression of M2 markers in macrophages. Concomitant with increased expression of proinflammatory cytokines, such as IL-1b and IL-18, markers of inflammasome activation also increased in the macrophages of diabetic miR-146a 2/2 mice. These studies suggest that in early DN, miR-146a upregulation exerts a protective effect by downregulating target inflammation-related genes, resulting in suppression of proinflammatory and inflammasome gene activation. Loss of this protective mechanism in miR-146a 2/2 mice leads to accelerated DN. Taken together, these results identify miR-146a as a novel anti-inflammatory noncoding RNA modulator of DN. 27: 227727: -228827: , 201627: . doi: 10.1681 Diabetic nephropathy (DN) is the leading cause of CKD and ESRD. 1-6 Development and progression of DN involve a complex interplay among metabolic, hemodynamic, growth, and inflammatory factors. 1,3,[7][8][9][10][11][12][13] The progressive decline in renal function during DN is a result of a multitude of pathologic changes in the kidneys, including glomerular and tubular hypertrophy, macrophage infiltration, extracellular matrix (ECM) accumulation in multiple renal cells, mesangial expansion, endothelial dysfunction, and podocyte injury. 1,3,[7][8][9][10][11][12][14][15][16] These pathologic changes clinically manifest as proteinuria and a steady deterioration in GFR. 3,4,16 Identification of molecular pathways that contribute to the pathophysiology of DN is imperative for the development of new therapeutic strategies. J Am Soc NephrolConversely, identification of factors that exert adaptive and protective roles in the early stages of DN can be exploited to prevent progression to ESRD.

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“…5) and new contributions to immune function and miR regulation are being discovered on an ongoing basis [216][217][218][219][220]. Understanding the molecular mechanisms of thrombin contribution to metastasis may help to develop efficient therapy and combat cancer.…”

Section: Discussionmentioning

confidence: 99%

Thrombin—unique coagulation system protein with multifaceted impacts on cancer and metastasis

Wojtukiewicz

Hempel

Sierko

et al. 2016

Cancer Metastasis Rev

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The association between blood coagulation and cancer development is well recognized. Thrombin, the pleiotropic enzyme best known for its contribution to fibrin formation and platelet aggregation during vascular hemostasis, may also trigger cellular events through protease-activated receptors, PAR-1 and PAR-4, leading to cancer progression. Our pioneering findings provided evidence that thrombin contributes to cancer metastasis by increasing adhesive potential of malignant cells. However, there is evidence that thrombin regulates every step of cancer dissemination: (1) cancer cell invasion, detachment from primary tumor, migration; (2) entering the blood vessel; (3) surviving in vasculature; (4) extravasation; (5) implantation in host organs. Recent studies have provided new molecular data about thrombin generation in cancer patients and the mechanisms by which thrombin contributes to transendothelial migration, platelet/tumor cell interactions, angiogenesis, and other processes. Though a great deal is known regarding the role of thrombin in cancer dissemination, there are new data for multiple thrombin-mediated events that justify devoting focus to this topic with a comprehensive approach.

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MicroRNA-146a Decreases High Glucose/Thrombin-Induced Endothelial Inflammation by Inhibiting NAPDH Oxidase 4 Expression

Cited by 77 publications

References 52 publications

The MicroRNAs in the Pathogenesis of Metabolic Memory

The MicroRNAs in the Pathogenesis of Metabolic Memory

Anti-Inflammatory Role of MicroRNA-146a in the Pathogenesis of Diabetic Nephropathy

Thrombin—unique coagulation system protein with multifaceted impacts on cancer and metastasis

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