When ER stress reaches a dead end

Urra, Hery; Dufey, Estefanie; Lisbona, Fernanda; Rojas‐Rivera, Diego; Hetz, Claudio

doi:10.1016/j.bbamcr.2013.07.024

Cited by 404 publications

(310 citation statements)

References 169 publications

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“…In the present study, we develop evidence that ER stress pathways may be an important regulator of JNK activation in the vasculature in patients with DM by demonstrating increased activation of both the IRE1α and PERK pathways. Prolonged ER stress results in the induction of the pro‐apoptotic transcription factor CHOP, regarded as a key mediator of cell death, endothelial impairment, and disease in response to ER overload 27, 46, 47, 48. In the present study, we showed an enhanced expression of CHOP in the vascular endothelium of patients with DM when compared with controls without DM.…”

Section: Discussionsupporting

confidence: 62%

“…Although acute ER stress activation could be beneficial for the cell, chronic ER stress results in an increased translation of ATF4, which promotes the upregulation of genes involved in oxidative stress and apoptosis. Chronic ER stress results in an elevated expression of the pro‐apoptotic transcription factor CHOP 27. Endothelial cells from patients with DM showed higher CHOP expression compared with controls without DM (* P =0.02) (Figure 2), suggesting that DM is associated with a chronic ER stress activation and the activation of apoptotic signaling pathways in the vascular endothelium.…”

Section: Resultsmentioning

confidence: 98%

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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: Discussionsupporting

confidence: 62%

Section: Resultsmentioning

confidence: 98%

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

Bretón‐Romero

Weisbrod

Feng

et al. 2018

JAHA

View full text Add to dashboard Cite

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“…An important feature of apoptosis is the activation of caspases where the Bcl-2 family plays a crucial role in regulating their engagement under ER stress [42]. In our study, we observed that HO-1 induction protected HUVECs against high glucose-induced activation of caspases 3 and 7.…”

Section: Discussionsupporting

confidence: 62%

Heme oxygenase (HO)-1 induction prevents Endoplasmic Reticulum stress-mediated endothelial cell death and impaired angiogenic capacity

Maamoun

Zachariah

McVey

et al. 2017

Biochemical Pharmacology

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Most of diabetic cardiovascular complications are attributed to endothelial dysfunction and impaired angiogenesis. Endoplasmic Reticulum (ER) and oxidative stresses were shown to play a pivotal role in the development of endothelial dysfunction in diabetes.Hemeoxygenase-1 (HO-1) was shown to protect against oxidative stress in diabetes; however, its role in alleviating ER stress-induced endothelial dysfunction remains not fully elucidated. We aim here to test the protective role of HO-1 against high glucose-mediated ER stress and endothelial dysfunction and understand the underlying mechanisms with special emphasis on oxidative stress, inflammation and cell death. Altogether, we show here the critical role of ER stress-mediated cell death in diabetesinduced endothelial dysfunction and impaired angiogenesis and underscore the role of HO-1 induction as a key therapeutic modulator for ER stress response in ischemic disorders and diabetes. Our results also highlight the complex interplay between ER stress response and oxidative stress.

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“…Other examples of crosstalk between trafficking events and apoptosis exist (e.g., ER [147][148][149], Golgi [150]) suggesting that much more is to be uncovered on the reciprocity between apoptosis and intracellular trafficking. For a detailed discussion on organelle remodeling during cell death and crosstalk between organelle status and the apoptotic machinery, see Cheng & Lane [151].…”

Section: Discussionmentioning

confidence: 99%

Caspases rule the intracellular trafficking cartel

2017

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During apoptosis, caspases feast on several hundreds of cellular proteins to orchestrate rapid cellular demise. Indeed, caspases are known to get a taste of every cellular process in one way or another, activating some, but most often shutting them down. Thus, it is not surprising that caspases proteolyze proteins involved in intracellular trafficking with particularly devastating consequences for this important process. This review article focuses on how caspases target the machinery responsible for smuggling goods within and outside the cell.

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When ER stress reaches a dead end

Cited by 404 publications

References 169 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

Heme oxygenase (HO)-1 induction prevents Endoplasmic Reticulum stress-mediated endothelial cell death and impaired angiogenic capacity

Caspases rule the intracellular trafficking cartel

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