scholarly journals Apelin-13 Inhibits Methylglyoxal-Induced Unfolded Protein Responses and Endothelial Dysfunction via Regulating AMPK Pathway

2020 ◽  
Vol 21 (11) ◽  
pp. 4069 ◽  
Author(s):  
Sujin Kim ◽  
Suji Kim ◽  
Ae-Rang Hwang ◽  
Hyoung Chul Choi ◽  
Ji-Yun Lee ◽  
...  
Keyword(s):  
Endothelial Dysfunction ◽  
Er Stress ◽  
Therapeutic Potential ◽  
Ex Vivo ◽  
Cardiovascular Complications ◽  
Unfolded Protein Responses ◽  
Unfolded Protein ◽  
Endothelial Apoptosis ◽  
Ampk Pathway ◽  
Aortic Endothelial

It has been suggested that methylglyoxal (MGO), a glycolytic metabolite, has more detrimental effects on endothelial dysfunction than glucose itself. Recent reports showed that high glucose and MGO induced endoplasmic reticulum (ER) stress and myocyte apoptosis in ischemic heart disease was inhibited by apelin. The goal of the study is to investigate the molecular mechanism by which MGO induces endothelial dysfunction via the regulation of ER stress in endothelial cells, and to examine whether apelin-13, a cytoprotective polypeptide ligand, protects MGO-induced aortic endothelial dysfunction. MGO-induced ER stress and apoptosis were determined by immunoblotting and MTT assay in HUVECs. Aortic endothelial dysfunction was addressed by en face immunostaining and acetylcholine-induced vasodilation analysis with aortic rings from mice treated with MGO in the presence or absence of apelin ex vivo. TUDCA, an inhibitor of ER stress, inhibited MGO-induced apoptosis and reduction of cell viability, suggesting that MGO signaling to endothelial apoptosis is mediated via ER stress, which leads to activation of unfolded protein responses (UPR). In addition, MGO-induced UPR and aortic endothelial dysfunction were significantly diminished by apelin-13. Finally, this study showed that apelin-13 protects MGO-induced UPR and endothelial apoptosis through the AMPK pathway. Apelin-13 reduces MGO-induced UPR and endothelial dysfunction via regulating the AMPK activating pathway, suggesting the therapeutic potential of apelin-13 in diabetic cardiovascular complications.

scholarly journals Coptisine Attenuates Diabetes—Associated Endothelial Dysfunction through Inhibition of Endoplasmic Reticulum Stress and Oxidative Stress

Molecules ◽  
2021 ◽  
Vol 26 (14) ◽  
pp. 4210
Author(s):  
Yan Zhou ◽  
Chunxiu Zhou ◽  
Xutao Zhang ◽  
Chi Teng Vong ◽  
Yitao Wang ◽  
...  
Keyword(s):  
Oxidative Stress ◽  
Risk Factors ◽  
Endoplasmic Reticulum ◽  
Er Stress ◽  
Vascular Function ◽  
Inflammatory Responses ◽  
Therapeutic Potential ◽  
Ex Vivo ◽  
Diabetic Mice ◽  
And Oxidative Stress

Coptisine is the major bioactive protoberberine alkaloid found in Rhizoma Coptidis. Coptisine reduces inflammatory responses and improves glucose tolerance; nevertheless, whether coptisine has vasoprotective effect in diabetes is not fully characterized. Conduit arteries including aortas and carotid arteries were obtained from male C57BL/6J mice for ex vivo treatment with risk factors (high glucose or tunicamycin) and coptisine. Some arterial rings were obtained from diabetic mice, which were induced by high-fat diet (45% kcal% fat) feeding for 6 weeks combined with a low-dose intraperitoneal injection of streptozotocin (120 mg/kg). Functional studies showed that coptisine protected endothelium-dependent relaxation in aortas against risk factors and from diabetic mice. Coptisine increased phosphorylations of AMPK and eNOS and downregulated the endoplasmic reticulum (ER) stress markers as determined by Western blotting. Coptisine elevates NO bioavailability and decreases reactive oxygen species level. The results indicate that coptisine improves vascular function in diabetes through suppression of ER stress and oxidative stress, implying the therapeutic potential of coptisine to treat diabetic vasculopathy.

scholarly journals Endothelial Dysfunction in Diabetes Mellitus: Possible Involvement of Endoplasmic Reticulum Stress?

2012 ◽  
Vol 2012 ◽  
pp. 1-14 ◽  
Author(s):  
Basma Basha ◽  
Samson Mathews Samuel ◽  
Chris R. Triggle ◽  
Hong Ding
Keyword(s):  
Oxidative Stress ◽  
Diabetes Mellitus ◽  
Clinical Trials ◽  
Endoplasmic Reticulum ◽  
Endothelial Dysfunction ◽  
Er Stress ◽  
Vascular Complications ◽  
Cardiovascular Complications ◽  
Therapeutic Agents ◽  
Recent Past

The vascular complications of diabetes mellitus impose a huge burden on the management of this disease. The higher incidence of cardiovascular complications and the unfavorable prognosis among diabetic individuals who develop such complications have been correlated to the hyperglycemia-induced oxidative stress and associated endothelial dysfunction. Although antioxidants may be considered as effective therapeutic agents to relieve oxidative stress and protect the endothelium, recent clinical trials involving these agents have shown limited therapeutic efficacy in this regard. In the recent past experimental evidence suggest that endoplasmic reticulum (ER) stress in the endothelial cells might be an important contributor to diabetes-related vascular complications. The current paper contemplates the possibility of the involvement of ER stress in endothelial dysfunction and diabetes-associated vascular complications.

Effects of ER stress on unfolded protein responses, cell survival, and viral replication in primary effusion lymphoma

2016 ◽  
Vol 469 (3) ◽  
pp. 565-572 ◽  
Author(s):  
Zenpei Shigemi ◽  
Yusuke Baba ◽  
Naoko Hara ◽  
Jumpei Matsuhiro ◽  
Hiroki Kagawa ◽  
...  
Keyword(s):  
Viral Replication ◽  
Er Stress ◽  
Cell Survival ◽  
Primary Effusion Lymphoma ◽  
Unfolded Protein Responses ◽  
Unfolded Protein

scholarly journals Endoplasmic Reticulum Stress and Lipid Metabolism: Mechanisms and Therapeutic Potential

2012 ◽  
Vol 2012 ◽  
pp. 1-13 ◽  
Author(s):  
Sana Basseri ◽  
Richard C. Austin
Keyword(s):  
Endoplasmic Reticulum ◽  
Protein Folding ◽  
Lipid Metabolism ◽  
Er Stress ◽  
Therapeutic Potential ◽  
Critical Role ◽  
Signal Transduction Pathway ◽  
Unfolded Protein ◽  
The Unfolded Protein Response ◽  
Stress Dependent

The endoplasmic reticulum (ER) plays a crucial role in protein folding, assembly, and secretion. Disruption of ER homeostasis may lead to accumulation of misfolded or unfolded proteins in the ER lumen, a condition referred to as ER stress. In response to ER stress, a signal transduction pathway known as the unfolded protein response (UPR) is activated. UPR activation allows the cell to cope with an increased protein-folding demand on the ER. Recent studies have shown that ER stress/UPR activation plays a critical role in lipid metabolism and homeostasis. ER-stress-dependent dysregulation of lipid metabolism may lead to dyslipidemia, insulin resistance, cardiovascular disease, type 2 diabetes, and obesity. In this paper, we examine recent findings illustrating the important role ER stress/UPR signalling pathways play in regulation of lipid metabolism, and how they may lead to dysregulation of lipid homeostasis.

scholarly journals Endoplasmic reticulum stress and the development of endothelial dysfunction

2017 ◽  
Vol 312 (3) ◽  
pp. H355-H367 ◽  
Author(s):  
M. L. Battson ◽  
D. M. Lee ◽  
C. L. Gentile
Keyword(s):  
Endoplasmic Reticulum ◽  
Endothelial Dysfunction ◽  
Er Stress ◽  
Critical Role ◽  
Unfolded Protein ◽  
Vasoactive Substances ◽  
Important Regulator ◽  
The Unfolded Protein Response ◽  
Protein Response ◽  
Er Homeostasis

The vascular endothelium plays a critical role in cardiovascular homeostasis, and thus identifying the underlying causes of endothelial dysfunction has important clinical implications. In this regard, the endoplasmic reticulum (ER) has recently emerged as an important regulator of metabolic processes. Dysfunction within the ER, broadly termed ER stress, evokes the unfolded protein response (UPR), an adaptive pathway that aims to restore ER homeostasis. Although the UPR is the first line of defense against ER stress, chronic activation of the UPR leads to cell dysfunction and death and has recently been implicated in the pathogenesis of endothelial dysfunction. Numerous risk factors for endothelial dysfunction can induce ER stress, which may in turn disrupt endothelial function via direct effects on endothelium-derived vasoactive substances or by activating other pathogenic cellular networks such as inflammation and oxidative stress. This review summarizes the available data linking ER stress to endothelial dysfunction.

scholarly journals Endothelial Dysfunction in Mice with Streptozotocin-induced Type 1 Diabetes Is Opposed by Compensatory Overexpression of Cyclooxygenase-2 in the Vasculature

Endocrinology ◽  
2009 ◽  
Vol 150 (2) ◽  
pp. 849-861 ◽  
Author(s):  
Carmela Nacci ◽  
Mariela Tarquinio ◽  
Leonarda De Benedictis ◽  
Annamaria Mauro ◽  
Addolorata Zigrino ◽  
...  
Keyword(s):  
Nitric Oxide ◽  
Type 1 Diabetes ◽  
Endothelial Dysfunction ◽  
Ex Vivo ◽  
Cardiovascular Complications ◽  
Cyclooxygenase 2 ◽  
Compensatory Mechanisms ◽  
Cox 2 ◽  
Expression And Activity

Cardiovascular complications of diabetes result from endothelial dysfunction secondary to persistent hyperglycemia. We investigated potential compensatory mechanisms in the vasculature that oppose endothelial dysfunction in diabetes. BALB/c mice were treated with streptozotocin (STZ) to induce type 1 diabetes (T1D). In mesenteric vascular beds (MVBs), isolated ex vivo from mice treated with STZ for 1 wk, dose-dependent vasorelaxation to acetylcholine (ACh) or sodium nitroprusside was comparable with that in age-matched control mice (CTRL). By contrast, MVBs from mice treated with STZ for 8 wk had severely impaired vasodilator responses to ACh consistent with endothelial dysfunction. Pretreatment of MVBs from CTRL mice with nitric oxide synthase inhibitor nearly abolished vasodilation to ACh. In MVB from 1-wk STZ-treated mice, vasodilation to ACh was only partially impaired by L-Nω-arginine methyl ester. Thus, vasculature of mice with T1D may have compensatory nitric oxide-independent mechanisms to augment vasodilation to ACh and oppose endothelial dysfunction. Indeed, pretreatment of MVBs isolated from 1-wk STZ-treated mice with NS-398 [selective cyclooxygenase (COX)-2 inhibitor] unmasked endothelial dysfunction not evident in CTRL mice pretreated without or with NS-398. Expression of COX-2 in MVBs, aortic endothelial cells, and aortic vascular smooth muscle cells from STZ-treated mice was significantly increased (vs. CTRL). Moreover, concentrations of the COX-2-dependent vasodilator 6-keto-prostaglandin F-1α was elevated in conditioned media from aorta of STZ-treated mice. We conclude that endothelial dysfunction in a mouse model of T1D is opposed by compensatory up-regulation of COX-2 expression and activity in the vasculature that may be relevant to developing novel therapeutic strategies for diabetes and its cardiovascular complications. Endothelial dysfunction in type 1 diabetes is opposed by compensatory mechanisms involving increased expression and activity of cyclooxygenase-2 in the vasculature induced by pro-inflammatory signaling.

The balance between adaptive and apoptotic unfolded protein responses regulates β-cell death under ER stress conditions through XBP1, CHOP and JNK

2015 ◽  
Vol 413 ◽  
pp. 189-201 ◽  
Author(s):  
Jeng Yie Chan ◽  
Jude Luzuriaga ◽  
Emma L. Maxwell ◽  
Phillip K. West ◽  
Mohammed Bensellam ◽  
...  
Keyword(s):  
Cell Death ◽  
Er Stress ◽  
Stress Conditions ◽  
Β Cell ◽  
Unfolded Protein Responses ◽  
Unfolded Protein

scholarly journals ESCRT-III-driven piecemeal micro-ER-phagy remodels the ER during recovery from ER stress

2019 ◽  
Vol 10 (1) ◽  
Author(s):  
Marisa Loi ◽  
Andrea Raimondi ◽  
Diego Morone ◽  
Maurizio Molinari
Keyword(s):  
Endoplasmic Reticulum ◽  
Er Stress ◽  
Molecular Chaperones ◽  
Binding Activity ◽  
Catabolic Pathway ◽  
Unfolded Protein Responses ◽  
Genetic Analyses ◽  
Endosomal Sorting ◽  
Unfolded Protein ◽  
And Function

Abstract The endoplasmic reticulum (ER) produces about 40% of the nucleated cell’s proteome. ER size and content in molecular chaperones increase upon physiologic and pathologic stresses on activation of unfolded protein responses (UPR). On stress resolution, the mammalian ER is remodeled to pre-stress, physiologic size and function on activation of the LC3-binding activity of the translocon component SEC62. This elicits recov-ER-phagy, i.e., the delivery of the excess ER generated during the phase of stress to endolysosomes (EL) for clearance. Here, ultrastructural and genetic analyses reveal that recov-ER-phagy entails the LC3 lipidation machinery and proceeds via piecemeal micro-ER-phagy, where RAB7/LAMP1-positive EL directly engulf excess ER in processes that rely on the Endosomal Sorting Complex Required for Transport (ESCRT)-III component CHMP4B and the accessory AAA+ ATPase VPS4A. Thus, ESCRT-III-driven micro-ER-phagy emerges as a key catabolic pathway activated to remodel the mammalian ER on recovery from ER stress.

Endoplasmic reticulum stress in disease: mechanisms and therapeutic opportunities

2009 ◽  
Vol 118 (1) ◽  
pp. 19-29 ◽  
Author(s):  
Toru Hosoi ◽  
Koichiro Ozawa
Keyword(s):  
Endoplasmic Reticulum ◽  
Endoplasmic Reticulum Stress ◽  
Neurodegenerative Diseases ◽  
Er Stress ◽  
Therapeutic Potential ◽  
Unfolded Protein ◽  
Pathological Conditions ◽  
Disease Mechanisms ◽  
Obesity And Diabetes ◽  
Protein Response

Various stresses, which impair ER (endoplasmic reticulum) function, lead to an accumulation of unfolded or misfolded proteins. ER stress triggers many rescuer responses, including a UPR (unfolded protein response). Increasing evidence has suggested that ER stress is involved in neurodegenerative diseases (Alzheimer's disease, Parkinson's disease and cerebral ischaemic insults), cancer, obesity and diabetes. In the present review, we consider the importance of ER stress under pathological conditions in mammals. Furthermore, we discuss the therapeutic potential for treatment targeting ER stress.

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