High glucose condition increases NADPH oxidase activity in endothelial microparticles that promote vascular inflammation

Jansen, Felix; Yang, Xiaoyan; Hoelscher, M; Nickenig, Georg; Werner, Nikos

doi:10.1093/eurheartj/eht309.p3261

Cited by 22 publications

(26 citation statements)

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“…On a molecular level, our results complement findings from Rautou et al, who demonstrated that the effect of human MP depends on the stage of disease progression in patients with atherosclerosis and liver cirrhosis [38,39]. Recently, we showed that iEMP promote ICAM-1 and VCAM-1 expression in resting endothelial target cells [34]. In this study, we found that under pro-inflammatory conditions, iEMP rather reduce ICAM-1 expression in target ECs.…”

Section: Discussionsupporting

confidence: 89%

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Endothelial microparticles reduce ICAM‐1 expression in a microRNA‐222‐dependent mechanism

Jansen

Yang

Baumann

et al. 2015

J Cellular Molecular Medi

106

102

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Endothelial microparticles (EMP) are released from activated or apoptotic endothelial cells (ECs) and can be taken up by adjacent ECs, but their effect on vascular inflammation after engulfment is largely unknown. We sought to determine the role of EMP in EC inflammation. In vitro, EMP treatment significantly reduced tumour necrosis factor-α-induced endothelial intercellular adhesion molecule (ICAM)-1 expression on mRNA and protein level, whereas there was no effect on vascular cell adhesion molecule-1 expression. Reduced ICAM-1 expression after EMP treatment resulted in diminished monocyte adhesion in vitro. In vivo, systemic treatment of ApoE−/− mice with EMP significantly reduced murine endothelial ICAM-1 expression. To explore the underlying mechanisms, Taqman microRNA array was performed and microRNA (miR)-222 was identified as the strongest regulated miR between EMP and ECs. Following experiments demonstrated that miR-222 was transported into recipient ECs by EMP and functionally regulated expression of its target protein ICAM-1 in vitro and in vivo. After simulating diabetic conditions, EMP derived from glucose-treated ECs contained significantly lower amounts of miR-222 and showed reduced anti-inflammatory capacity in vitro and in vivo. Finally, circulating miR-222 level was diminished in patients with coronary artery disease (CAD) compared to patients without CAD. EMPs promote anti-inflammatory effects in vitro and in vivo by reducing endothelial ICAM-1 expression via the transfer of functional miR-222 into recipient cells. In pathological hyperglycaemic conditions, EMP-mediated miR-222-dependent anti-inflammatory effects are reduced.

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Section: Discussionsupporting

confidence: 89%

“…However, evidence suggest that the effect of EMP on target cells depends on the condition of the releasing cell [34]. We found that iEMP derived under high glucose conditions show significantly reduced miR-222 expression and reduced anti-inflammatory capacity in vitro compared to EMP derived from untreated cells.…”

Section: Discussionmentioning

confidence: 62%

Endothelial microparticles reduce ICAM‐1 expression in a microRNA‐222‐dependent mechanism

Jansen

Yang

Baumann

et al. 2015

J Cellular Molecular Medi

106

102

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“…It is known that hyperglycemia induces MAPK-p38 activation in endothelial cells and that p38 inhibition prevents endothelial cell damage by hyperglycemia. 48 Thus, this evidence also suggests that a mechanism similar to that underlying CA-II increase in myocytes by DM may also explain CA-I increase in endothelial cells by DM. Of course, this hypothesis remains highly speculative, and it remains to be properly tested in future studies.…”

Section: Limitationsmentioning

confidence: 58%

Carbonic Anhydrase Activation Is Associated With Worsened Pathological Remodeling in Human Ischemic Diabetic Cardiomyopathy

Torella

Ellison

Torella

et al. 2014

JAHA

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BackgroundDiabetes mellitus (DM) has multifactorial detrimental effects on myocardial tissue. Recently, carbonic anhydrases (CAs) have been shown to play a major role in diabetic microangiopathy but their role in the diabetic cardiomyopathy is still unknown.Methods and ResultsWe obtained left ventricular samples from patients with DM type 2 (DM‐T2) and nondiabetic (NDM) patients with postinfarct heart failure who were undergoing surgical coronary revascularization. Myocardial levels of CA‐I and CA‐II were 6‐ and 11‐fold higher, respectively, in DM‐T2 versus NDM patients. Elevated CA‐I expression was mainly localized in the cardiac interstitium and endothelial cells. CA‐I induced by high glucose levels hampers endothelial cell permeability and determines endothelial cell apoptosis in vitro. Accordingly, capillary density was significantly lower in the DM‐T2 myocardial samples (mean±SE=2152±146 versus 4545±211/mm2). On the other hand, CA‐II was mainly upregulated in cardiomyocytes. The latter was associated with sodium‐hydrogen exchanger‐1 hyperphosphorylation, exaggerated myocyte hypertrophy (cross‐sectional area 565±34 versus 412±27 μm2), and apoptotic death (830±54 versus 470±34 per 106 myocytes) in DM‐T2 versus NDM patients. CA‐II is activated by high glucose levels and directly induces cardiomyocyte hypertrophy and death in vitro, which are prevented by sodium‐hydrogen exchanger‐1 inhibition. CA‐II was shown to be a direct target for repression by microRNA‐23b, which was downregulated in myocardial samples from DM‐T2 patients. MicroRNA‐23b is regulated by p38 mitogen‐activated protein kinase, and it modulates high‐glucose CA‐II–dependent effects on cardiomyocyte survival in vitro.ConclusionsMyocardial CA activation is significantly elevated in human diabetic ischemic cardiomyopathy. These data may open new avenues for targeted treatment of diabetic heart failure.

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“…Diabetes is known to increase circulating MV levels, but, in contrast, these MVs seem to be severely impaired in terms of modulating biological actions. 15,38 In our cohort, CAD patients with diabetes had significantly higher annexin V-and CD31positive MVs compared with nondiabetic patients. When comparing MmiR-126 and MmiR-199a levels in CAD patients with and without diabetes, we were able to show that the diabetic subgroup had significantly lower MmiR-126 and MmiR-199a levels compared with euglycemic patients (P=0.017 15 and P=0.034, respectively) ( Figure 7).…”

Section: Discussionmentioning

confidence: 74%

MicroRNA Expression in Circulating Microvesicles Predicts Cardiovascular Events in Patients With Coronary Artery Disease

Jansen

Yang

Proebsting

et al. 2014

JAHA

268

203

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BackgroundCirculating microRNAs (miRNAs) are differentially regulated and selectively packaged in microvesicles (MVs). We evaluated whether circulating vascular and endothelial miRNAs in patients with stable coronary artery disease have prognostic value for the occurrence of cardiovascular (CV) events.Methods and ResultsTen miRNAs involved in the regulation of vascular performance—miR‐126, miR‐222, miR‐let7d, miR‐21, miR‐20a, miR‐27a, miR‐92a, miR‐17, miR‐130, and miR‐199a—were quantified in plasma and circulating MVs by reverse transcription polymerase chain reaction in 181 patients with stable coronary artery disease. The median duration of follow‐up for major adverse CV event–free survival was 6.1 years (range: 6.0–6.4 years). Events occurred in 55 patients (31.3%). There was no significant association between CV events and plasma level of the selected miRNAs. In contrast, increased expression of miR‐126 and miR‐199a in circulating MVs was significantly associated with a lower major adverse CV event rate. In univariate analysis, above‐median levels of miR‐126 in circulating MVs were predictors of major adverse CV event–free survival (hazard ratio: 0.485 [95% CI: 0.278 to 0.846]; P=0.007) and percutaneous coronary interventions (hazard ratio: 0.458 [95% CI: 0.222 to 0.945]; P=0.03). Likewise, an increased level of miR‐199a in circulating MVs was associated with a reduced risk of major adverse CV events (hazard ratio: 0.518 [95% CI: 0.299 to 0.898]; P=0.01) and revascularization (hazard ratio: 0.439 [95% CI: 0.232 to 0.832]; P=0.01) in univariate analysis. miRNA expression analysis in plasma compartments revealed that miR‐126 and miR‐199a are present mainly in circulating MVs. MV‐sorting experiments showed that endothelial cells and platelets were found to be the major cell sources of MVs containing miR‐126 and miR‐199a, respectively.ConclusionMVs containing miR‐126 and miR‐199a but not freely circulating miRNA expression predict the occurrence of CV events in patients with stable coronary artery disease.

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High glucose condition increases NADPH oxidase activity in endothelial microparticles that promote vascular inflammation

Cited by 22 publications

References 0 publications

Endothelial microparticles reduce ICAM‐1 expression in a microRNA‐222‐dependent mechanism

Endothelial microparticles reduce ICAM‐1 expression in a microRNA‐222‐dependent mechanism

Carbonic Anhydrase Activation Is Associated With Worsened Pathological Remodeling in Human Ischemic Diabetic Cardiomyopathy

MicroRNA Expression in Circulating Microvesicles Predicts Cardiovascular Events in Patients With Coronary Artery Disease

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