Altered Mitochondrial Dynamics Contributes to Endothelial Dysfunction in Diabetes Mellitus

Shenouda, Sherene M.; Widlansky, Michael E.; Chen, Kai; Xu, Guoquan; Holbrook, Monika; Tabit, Corey E.; Hamburg, Naomi M.; Frame, Alissa A.; Caiano, Tara; Kluge, Matthew A.; Duess, Mai‐Ann; Levit, Aaron; Kim, Brian; Hartman, Mor-Li; Joseph, Lija; Shirihai, Orian S.; Vita, Joseph A.

doi:10.1161/circulationaha.110.014506

Cited by 453 publications

(450 citation statements)

References 29 publications

(44 reference statements)

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“…Peripheral venous endothelial cell biopsies were performed as previously described 22, 23. Briefly, a 20‐gauge intravenous catheter was placed in a superficial forearm vein using aseptic technique.…”

Section: Methodsmentioning

confidence: 99%

Liraglutide Treatment Reduces Endothelial Endoplasmic Reticulum Stress and Insulin Resistance in Patients With Diabetes Mellitus

Bretón‐Romero

Weisbrod

Feng

et al. 2018

JAHA

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BackgroundPrior studies have shown that nutrient excess induces endoplasmic reticulum (ER) stress in nonvascular tissues from patients with diabetes mellitus (DM). ER stress and the subsequent unfolded protein response may be protective, but sustained activation may drive vascular injury. Whether ER stress contributes to endothelial dysfunction in patients with DM remains unknown.Methods and ResultsTo characterize vascular ER stress, we isolated endothelial cells from 42 patients with DM and 37 subjects without DM. Endothelial cells from patients with DM displayed higher levels of ER stress markers compared with controls without DM. Both the early adaptive response, evidenced by higher phosphorylated protein kinase–like ER eukaryotic initiation factor‐2a kinase and inositol‐requiring ER‐to‐nucleus signaling protein 1 (P=0.02, P=0.007, respectively), and the chronic ER stress response evidenced by higher C/EBPα‐homologous protein (P=0.02), were activated in patients with DM. Higher inositol‐requiring ER‐to‐nucleus signaling protein 1 activation was associated with lower flow–mediated dilation, consistent with endothelial dysfunction (r=0.53, P=0.02). Acute treatment with liraglutide, a glucagon‐like peptide 1 receptor agonist, reduced p‐inositol‐requiring ER‐to‐nucleus signaling protein 1 (P=0.01), and the activation of its downstream target c‐jun N‐terminal kinase (P=0.025) in endothelial cells from patients with DM. Furthermore, liraglutide restored insulin‐stimulated endothelial nitric oxide synthase activation in patients with DM (P=0.019).ConclusionsIn summary, our data suggest that ER stress contributes to vascular insulin resistance and endothelial dysfunction in patients with DM. Further, we have demonstrated that liraglutide ameliorates ER stress, decreases c‐jun N‐terminal kinase activation and restores insulin‐mediated endothelial nitric oxide synthase activation in endothelial cells from patients with DM.

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Section: Methodsmentioning

confidence: 99%

Liraglutide Treatment Reduces Endothelial Endoplasmic Reticulum Stress and Insulin Resistance in Patients With Diabetes Mellitus

Bretón‐Romero

Weisbrod

Feng

et al. 2018

JAHA

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“…In Vivo UnAG Protects Vessels Against ROS Production by Inducing SOD-2 Impaired antioxidant machinery and increased ROS production are crucial mediators of vascular damage in diabetes (36). This is particularly true in PAD patients (37), and so ECs recovered from ischemic muscles were first evaluated for intracellular ROS content.…”

Section: Unag Protects Ob/ob Muscles Against Hind Limb Ischemiamentioning

confidence: 99%

Unacylated Ghrelin Induces Oxidative Stress Resistance in a Glucose Intolerance and Peripheral Artery Disease Mouse Model by Restoring Endothelial Cell miR-126 Expression

et al. 2014

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Reactive oxygen species (ROS) are crucial in longterm diabetes complications, including peripheral artery disease (PAD). In this study, we have investigated the potential clinical impact of unacylated ghrelin (UnAG) in a glucose intolerance and PAD mouse model. We demonstrate that UnAG is able to protect skeletal muscle and endothelial cells (ECs) from ROS imbalance in hind limb ischemiasubjected ob/ob mice. This effect translates into reductions in hind limb functional impairment. We show that UnAG rescues sirtuin 1 (SIRT1) activity and superoxide dismutase-2 (SOD-2) expression in ECs. This leads to SIRT1-mediated p53 and histone 3 lysate 56 deacetylation and results in reduced EC senescence in vivo. We demonstrate, using small interfering RNA technology, that SIRT1 is also crucial for SOD-2 expression. UnAG also renews micro-RNA (miR)-126 expression, resulting in the posttranscriptional regulation of vascular cell adhesion molecule 1 expression and a reduced number of infiltrating inflammatory cells in vivo. Loss-of-function experiments that target miR-126 demonstrate that miR-126 also controls SIRT1 and SOD-2 expression, thus confirming its role in driving UnAG-mediated EC protection against ROS imbalance. These results indicate that UnAG protects vessels from ROS imbalance in ob/ob mice by rescuing miR-126 expression, thus emphasizing its potential clinical impact in avoiding limb loss in PAD.

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“…Mitochondrial fission is essential for organelle and cell viability (1), and altered fission contributes to a broad range of diseases, including neurodegeneration, diabetes, and cancer (2)(3)(4)(5)(6). Despite its significance, mitochondrial fission is not well understood beyond the identification of proteins involved.…”

mentioning

confidence: 99%

A Targeted Mutation Identified through pK Measurements Indicates a Postrecruitment Role for Fis1 in Yeast Mitochondrial Fission

Koppenol-Raab¹,

Harwig

Posey

et al. 2016

Journal of Biological Chemistry

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The tail-anchored protein Fis1 is implicated as a passive tether in yeast mitochondrial fission. We probed the functional role of Fis1 Glu-78, whose elevated side chain pK a suggests participation in protein interactions. Fis1 binds partners Mdv1 or Dnm1 tightly, but mutation E78A weakens Fis1 interaction with Mdv1, alters mitochondrial morphology, and abolishes fission in a growth assay. In fis1⌬ rescue experiments, Fis1-E78A causes a novel localization pattern in which Dnm1 uniformly coats the mitochondria. By contrast, Fis1-E78A at lower expression levels recruits Dnm1 into mitochondrial punctate structures but fails to support normal fission. Thus, Fis1 makes multiple interactions that support Dnm1 puncta formation and may be essential after this step, supporting a revised model for assembly of the mitochondrial fission machinery. The insights gained by mutating a residue with a perturbed pK a suggest that side chain pK a values inferred from routine NMR sample pH optimization could provide useful leads for functional investigations.

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Altered Mitochondrial Dynamics Contributes to Endothelial Dysfunction in Diabetes Mellitus

Cited by 453 publications

References 29 publications

Liraglutide Treatment Reduces Endothelial Endoplasmic Reticulum Stress and Insulin Resistance in Patients With Diabetes Mellitus

Liraglutide Treatment Reduces Endothelial Endoplasmic Reticulum Stress and Insulin Resistance in Patients With Diabetes Mellitus

Unacylated Ghrelin Induces Oxidative Stress Resistance in a Glucose Intolerance and Peripheral Artery Disease Mouse Model by Restoring Endothelial Cell miR-126 Expression

A Targeted Mutation Identified through pK Measurements Indicates a Postrecruitment Role for Fis1 in Yeast Mitochondrial Fission

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