Abstract P118: Inhibition of Endoplasmic Reticulum Stress Prevents Intracranial Aneurysmal Rupture in a Mouse Model

Hypertension ◽  
2017 ◽  
Vol 70 (suppl_1) ◽  
Author(s):  
Daisuke Kudo ◽  
Hajime Furukawa ◽  
Satoru Eguchi ◽  
Tomoki Hashimoto
Keyword(s):  
Endoplasmic Reticulum ◽  
Angiotensin Ii ◽  
Mouse Model ◽  
Er Stress ◽  
Intracranial Aneurysms ◽  
Vehicle Group ◽  
Systemic Hypertension ◽  
Aneurysmal Rupture ◽  
Rupture Rate ◽  
Salt Hypertension

Background: Aneurysmal subarachnoid hemorrhage (SAH) can cause significant mortality and morbidity. To develop a therapy for prevention of intracranial aneurysmal rupture and subsequent SAH, it is important to clarify the mechanism of intracranial aneurysmal rupture. Stimulation of the renin-angiotensin system (RAS) causes hypertension and cardiovascular remodeling. Recent evidence shows that angiotensin II enhances endoplasmic reticulum (ER) stress and inhibition of ER stress prevents angiotensin II-induced vascular remodeling but not hypertension in mice. RAS has also been implicated in intracranial aneurysms. We have previously shown that angiotensin II receptor blocker (losartan) prevented intracranial aneurysmal rupture in a mouse model without affecting systemic hypertension. To clarify the mechanism of intracranial aneurysmal rupture via RAS, we have tested our hypothesis that inhibition of ER stress prevents intracranial aneurysmal rupture in a mouse model. Method: We used a mouse model of intracranial aneurysms in which spontaneous aneurysmal rupture causes neurologic symptoms. Intracranial aneurysms were induced in wild type mice by a single stereotactic injection of elastase (35mU) into the cerebrospinal fluid at right basal cistern and deoxycorticosterone (DOCA)-salt hypertension. Vehicle or 4-phenylbutyric acid (PBA, ER stress inhibitor , 100mg/kg/day) was subcutaneously injected into all mice once a day. To detect aneurysmal rupture, we performed daily neurological examinations. Symptomatic mice were euthanized immediately when they developed neurological symptoms, and all asymptomatic mice were euthanized 21 days after aneurysm induction. The incidence of aneurysms and rupture rate were compared between vehicle group and PBA group. Results: The incidence of aneurysms was not significantly different between two groups (100% in vehicle, 20 of 20 vs. 87% in PBA, 20 of 23, p=0.09). However, rupture rate was significantly lower in the PBA group (60%, 12 of 20) than the vehicle group (95%, 19 of 20). (p=0.008). Conclusion: Inhibition of ER stress reduced aneurysmal rupture in a mouse model of intracranial aneurysm induced by combination of elastase injection and DOCA-salt hypertension.

scholarly journals Endoplasmic reticulum and oxidant stress mediate nuclear factor-κB activation in the subfornical organ during angiotensin II hypertension

2015 ◽  
Vol 308 (10) ◽  
pp. C803-C812 ◽  
Author(s):  
Colin N. Young ◽  
Anfei Li ◽  
Frederick N. Dong ◽  
Julie A. Horwath ◽  
Catharine G. Clark ◽  
...  
Keyword(s):  
Blood Pressure ◽  
Endoplasmic Reticulum ◽  
Transcription Factor ◽  
Angiotensin Ii ◽  
Er Stress ◽  
Bioluminescence Imaging ◽  
Nuclear Factor Κb ◽  
Nuclear Factor ◽  
Ang Ii ◽  
Arterial Blood

Endoplasmic reticulum (ER) stress and reactive oxygen species (ROS) generation in the brain circumventricular subfornical organ (SFO) mediate the central hypertensive actions of Angiotensin II (ANG II). However, the downstream signaling events remain unclear. Here we tested the hypothesis that angiotensin type 1a receptors (AT1aR), ER stress, and ROS induce activation of the transcription factor nuclear factor-κB (NF-κB) during ANG II-dependent hypertension. To spatiotemporally track NF-κB activity in the SFO throughout the development of ANG II-dependent hypertension, we used SFO-targeted adenoviral delivery and longitudinal bioluminescence imaging in mice. During low-dose infusion of ANG II, bioluminescence imaging revealed a prehypertensive surge in NF-κB activity in the SFO at a time point prior to a significant rise in arterial blood pressure. SFO-targeted ablation of AT1aR, inhibition of ER stress, or adenoviral scavenging of ROS in the SFO prevented the ANG II-induced increase in SFO NF-κB. These findings highlight the utility of bioluminescence imaging to longitudinally track transcription factor activation during the development of ANG II-dependent hypertension and reveal an AT1aR-, ER stress-, and ROS-dependent prehypertensive surge in NF-κB activity in the SFO. Furthermore, the increase in NF-κB activity before a rise in arterial blood pressure suggests a causal role for SFO NF-κB in the development of ANG II-dependent hypertension.

scholarly journals MLN4924, a Protein Neddylation Inhibitor, Suppresses the Growth of Human Chondrosarcoma through Inhibiting Cell Proliferation and Inducing Endoplasmic Reticulum Stress-Related Apoptosis

2018 ◽  
Vol 20 (1) ◽  
pp. 72 ◽  
Author(s):  
Meng-Huang Wu ◽  
Ching-Yu Lee ◽  
Tsung-Jen Huang ◽  
Kuo-Yuan Huang ◽  
Chih-Hsin Tang ◽  
...  
Keyword(s):  
Cell Proliferation ◽  
Endoplasmic Reticulum ◽  
Mouse Model ◽  
Cell Viability ◽  
Er Stress ◽  
Cell Lines ◽  
Cell Cycles ◽  
Chondrosarcoma Cell ◽  
Xenograft Mouse Model ◽  
Human Chondrosarcoma

Chondrosarcoma, a heterogeneous malignant bone tumor, commonly produces cartilage matrix, which generally has no response to conventional therapies. Studies have reported that MLN4924, a NEDD8-activating enzyme inhibitor, achieves antitumor effects against numerous malignancies. In this study, the suppressive effects of MLN4924 on human chondrosarcoma cell lines were investigated using in vitro and in vivo assays, which involved measuring cell viability, cytotoxicity, apoptosis, proliferation, cell cycles, molecule-associated cell cycles, apoptosis, endoplasmic reticulum (ER) stress, and tumor growth in a xenograft mouse model. Our results demonstrated that MLN4924 significantly suppressed cell viability, exhibited cytotoxicity, and stimulated apoptosis through the activation of caspase-3 and caspase-7 in chondrosarcoma cell lines. Furthermore, MLN4924 significantly inhibited cell proliferation by diminishing the phosphorylation of histone H3 to cause G2/M cell cycle arrest. In addition, MLN4924 activated ER stress–related apoptosis by upregulating the phosphorylation of c-Jun N-terminal kinase (JNK), enhancing the expression of GRP78 and CCAAT-enhancer-binding protein homologous protein (CHOP, an inducer of endoplasmic ER stress–related apoptosis) and activating the cleavage of caspase-4. Moreover, MLN4924 considerably inhibited the growth of chondrosarcoma tumors in a xenograft mouse model. Finally, MLN4924-mediated antichondrosarcoma properties can be accompanied by the stimulation of ER stress–related apoptosis, implying that targeting neddylation by MLN4924 is a novel therapeutic strategy for treating chondrosarcoma.

Abstract 144: Roles of Aging and Cellular Senescence in Intracranial Aneurysm Rupture

Stroke ◽  
2020 ◽  
Vol 51 (Suppl_1) ◽  
Author(s):  
Hiroki Sato ◽  
Taichi Ikedo ◽  
Tetsuro Kimura ◽  
James Purcell ◽  
Samantha Merrow ◽  
...  
Keyword(s):  
Intracranial Aneurysm ◽  
Older Patients ◽  
Cerebral Arteries ◽  
Sirtuin 1 ◽  
Vehicle Group ◽  
Mrna Levels ◽  
Younger Patients ◽  
Aneurysmal Rupture ◽  
Rupture Rate ◽  
Increased Risk

Background: Aging is an independent risk factor for the rupture of intracranial aneurysm. One of the hallmarks of aging is chronic tissue inflammation. Sirtuin-1 keeps inflammation in check through the deacetylation of various proteins. It is well known that the levels of Sirtuin-1 in vascular tissues decrease with aging, resulting in chronic vascular inflammation. Age-dependent decrease in Sirtuin-1 may explain the link between aging and increased risk for aneurysmal rupture. Hypothesis: Reduction of Sirtuin-1 promotes aneurysmal rupture by inducing sustained aneurysmal wall inflammation. Methods: First, we assessed the levels of Sirtuin-1 expression in intracranial aneurysm tissues from patients older than 70 y.o. and compared with those from the younger patients (40 to 50 y.o.). Second, using a mouse model, we tested effects of Sirtuin-1 specific activator SRT1720 (15mg/kg/day) and specific inhibitor EX-527 (2.5mg/kg/day) on the development of aneurysmal rupture. In addition, we assessed the mRNA expression of inflammatory cytokines (IL-6, IL-1beta, MCP-1, and MMP-9) in cerebral arteries and aneurysms in mice treated with vehicle, SRT1720, or EX-527. Results: Sirtuin-1 expression levels in intracranial aneurysm tissues from the older patients were lower than those from the younger patients. The pharmacological inhibition of Sirtuin-1 increased rupture rate in mice (vehicle vs. EX-527: 58% vs. 88%, P <0.05). Moreover, the pharmacological activation of Sirtuin-1 reduced rupture rate in mice (vehicle vs. SRT1720: 80% vs. 50%, P <0.05). Levels of IL-6, MMP-9 mRNAs in cerebral arteries were significantly higher in the inhibitor group than in the vehicle group. On the other hand, both mRNA levels were lower in the activator group than in the vehicle group. Conclusions: Our findings suggest that the reduction of Sirtuin-1 promotes aneurysmal rupture via the induction of inflammation. This may explain the increased risk for aneurysmal subarachnoid hemorrhage in the older population. Our findings may become a basis for future studies to develop new therapies that target Sirtuin-1 for the prevention of aneurysmal rupture, especially in older patients.

Abstract 2817: Simvastatin Reduced The Rupture Of Intracranial Aneurysms In Mice

Stroke ◽  
2012 ◽  
Vol 43 (suppl_1) ◽  
Author(s):  
Elena I Liang ◽  
Yoshiteru Tada ◽  
Kosuke Wada ◽  
Hiroshi Makino ◽  
Mari Kudo ◽  
...  
Keyword(s):  
Intracranial Aneurysms ◽  
Vehicle Control ◽  
Superoxide Production ◽  
Protective Effects ◽  
Gelatinase Activity ◽  
Aneurysmal Rupture ◽  
Salt Hypertension ◽  
Anti Inflammatory ◽  
Lipophilic Statin ◽  
Oxidative Effects

Background and Purpose Subarachnoid hemorrhage resulting from the rupture of intracranial aneurysms causes severe morbidity and high mortality. Statins exert anti-inflammatory and anti-oxidative effects on the vasculature independent of their cholesterol-lowering properties. The protective effects of simvastatin, a common lipophilic statin, have been examined in various diseases. However, the role of statins on the rupture of intracranial aneurysms is still controversial. We hypothesized that simvastatin can prevent intracranial aneurysmal rupture. Methods Intracranial aneurysms were induced in male mice using a combination of a single injection of elastase into the cerebrospinal fluid and deoxycorticosterone acetate salt hypertension. Six days after aneurysm induction, daily treatments of vehicle control (n=32), and simvastatin (30mg/kg/day; n=32) were started. Mice were sacrificed when they developed neurological symptoms, or 21 days after aneurysm induction if mice did not have symptoms. In situ zymography and dihydroethidium staining were performed to detect gelatinase activity by matrix metalloproteinases (MMPs) and superoxide production, respectively. Results Simvastatin decreased the incidence of ruptured aneurysms ( Figure ) compared to vehicle control mice (28% vs. 63%, P<0.05). Simvastatin also improved the survival of mice with aneurysms. Simvastatin reduced superoxide production and gelatinase activity in aneurysmal walls, indicating that simvastatin treatment was effective. Conclusion Simvastatin reduced the incidence of intracranial aneurysmal rupture in mice. Furthermore, simvastatin reduced superoxide production and MMP-related gelatinase activity in aneurysmal walls. Simvastatin may have potentially protective effects against intracranial aneurysmal rupture via its anti-inflammatory and anti-oxidative properties..

scholarly journals Role of microRNA 690 in Mediating Angiotensin II Effects on Inflammation and Endoplasmic Reticulum Stress

Cells ◽  
2020 ◽  
Vol 9 (6) ◽  
pp. 1327
Author(s):  
Kalhara R. Menikdiwela ◽  
Latha Ramalingam ◽  
Mostafa M. Abbas ◽  
Halima Bensmail ◽  
Shane Scoggin ◽  
...  
Keyword(s):  
Endoplasmic Reticulum ◽  
Adipose Tissue ◽  
Angiotensin Ii ◽  
Er Stress ◽  
Mitogen Activated Protein Kinase ◽  
Luciferase Reporter ◽  
Small Rna Sequencing ◽  
Ang Ii ◽  
Protective Function

Overactivation of the renin–angiotensin system (RAS) during obesity disrupts adipocyte metabolic homeostasis and induces endoplasmic reticulum (ER) stress and inflammation; however, underlying mechanisms are not well known. We propose that overexpression of angiotensinogen (Agt), the precursor protein of RAS in adipose tissue or treatment of adipocytes with Angiotensin II (Ang II), RAS bioactive hormone, alters specific microRNAs (miRNA), that target ER stress and inflammation leading to adipocyte dysfunction. Epididymal white adipose tissue (WAT) from B6 wild type (Wt) and transgenic male mice overexpressing Agt (Agt-Tg) in adipose tissue and adipocytes treated with Ang II were used. Small RNA sequencing and microarray in WAT identified differentially expressed miRNAs and genes, out of which miR-690 and mitogen-activated protein kinase kinase 3 (MAP2K3) were validated as significantly up- and down-regulated, respectively, in Agt-Tg, and in Ang II-treated adipocytes compared to respective controls. Additionally, the direct regulatory role of miR-690 on MAP2K3 was confirmed using mimic, inhibitors and dual-luciferase reporter assay. Downstream protein targets of MAP2K3 which include p38, NF-κB, IL-6 and CHOP were all reduced. These results indicate a critical post-transcriptional role for miR-690 in inflammation and ER stress. In conclusion, miR-690 plays a protective function and could be a useful target to reduce obesity.

scholarly journals Androgens impair β-cell function in a mouse model of polycystic ovary syndrome by activating endoplasmic reticulum stress

2021 ◽  
Author(s):  
Bo Zhu ◽  
Yumei Chen ◽  
Fang Xu ◽  
Xiaolu Shen ◽  
Xuanyu Chen ◽  
...  
Keyword(s):  
Endoplasmic Reticulum ◽  
Polycystic Ovary Syndrome ◽  
Mouse Model ◽  
Er Stress ◽  
Cell Function ◽  
Polycystic Ovary ◽  
Β Cells ◽  
Β Cell ◽  
Ovary Syndrome ◽  
Β Cell Function

Background: Androgens excess results in endoplasmic reticulum (ER) stress, which is an important cause of β cells dysfunction. Here, we investigated the molecular regulation of androgens excess, ER stress, and β-cell function in polycystic ovary syndrome (PCOS). Methods: PCOS mouse model was established by injection of dehydroepiandrosterone (DHEA). Primary cultured mouse islets were used to detect testosterone (TE)-induced ER stress. The response of ER stress, apoptosis, and hyperinsulinemia were analyzed in INS-1 cells with or without TE exposure. Androgen receptor (AR) antagonist and ER stress inhibitor treatment was performed to evaluate the role of TE in ER stress and proinsulin secretion of PCOS mice. Results: PCOS mice had higher ER stress in islets. TE exposure induced ER stress and apoptosis significantly through sustaining insulin overexpression in β cells, which in turn impaired proinsulin maturation and secretion. Blocking this process could significantly relieve ER stress and apoptosis and improve insulin homeostasis. Conclusion: ER stress activated by androgens excess in PCOS contributes to β cell dysfunction and hyperinsulinemia.

scholarly journals Sex Difference and Rupture Rate of Intracranial Aneurysms: An Individual Patient Data Meta-Analysis

Stroke ◽  
2022 ◽  
Author(s):  
Charlotte C.M. Zuurbier ◽  
Rob Molenberg ◽  
Liselore A. Mensing ◽  
Marieke J.H. Wermer ◽  
Seppo Juvela ◽  
...  
Keyword(s):  
Risk Factors ◽  
Subarachnoid Hemorrhage ◽  
Sex Difference ◽  
Intracranial Aneurysms ◽  
Individual Patient Data ◽  
Meta Analysis ◽  
Patient Data ◽  
Aneurysmal Rupture ◽  
Rupture Rate ◽  
Related Risk

Background and Purpose: In previous studies, women had a higher risk of rupture of intracranial aneurysms than men, but female sex was not an independent risk factor. This may be explained by a higher prevalence of patient- or aneurysm-related risk factors for rupture in women than in men or by insufficient power of previous studies. We assessed sex differences in rupture rate taking into account other patient- and aneurysm-related risk factors for aneurysmal rupture. Methods: We searched Embase and Pubmed for articles published until December 1, 2020. Cohorts with available individual patient data were included in our meta-analysis. We compared rupture rates of women versus men using a Cox proportional hazard regression model adjusted for the PHASES score (Population, Hypertension, Age, Size of Aneurysm, Earlier Subarachnoid Hemorrhage From Another Aneurysm, Site of Aneurysm), smoking, and a positive family history of aneurysmal subarachnoid hemorrhage. Results: We pooled individual patient data from 9 cohorts totaling 9940 patients (6555 women, 66%) with 12 193 unruptured intracranial aneurysms, and 24 357 person-years follow-up. Rupture occurred in 163 women (rupture rate 1.04%/person-years [95% CI, 0.89–1.21]) and 63 men (rupture rate 0.74%/person-years [95% CI, 0.58–0.94]). Women were older (61.9 versus 59.5 years), were less often smokers (20% versus 44%), more often had internal carotid artery aneurysms (24% versus 17%), and larger sized aneurysms (≥7 mm, 24% versus 23%) than men. The unadjusted women-to-men hazard ratio was 1.43 (95% CI, 1.07–1.93) and the adjusted women/men ratio was 1.39 (95% CI, 1.02–1.90). Conclusions: Women have a higher risk of aneurysmal rupture than men and this sex difference is not explained by differences in patient- and aneurysm-related risk factors for aneurysmal rupture. Future studies should focus on the factors explaining the higher risk of aneurysmal rupture in women.

scholarly journals GanDouLing combined with Penicillamine improves cerebrovascular injury via PERK/eIF2α/CHOP endoplasmic reticulum stress pathway in the mouse model of Wilson’s disease

2018 ◽  
Vol 38 (5) ◽  
Author(s):  
Yonghua Chen ◽  
Bo Zhang ◽  
Shijian Cao ◽  
Wei Huang ◽  
Ni Liu ◽  
...  
Keyword(s):  
Endoplasmic Reticulum ◽  
Mouse Model ◽  
Er Stress ◽  
Vascular Injury ◽  
Caspase 3 ◽  
Wilson’S Disease ◽  
Wilson's Disease ◽  
Cerebrovascular Injury ◽  
Caspase 12 ◽  
Stress Pathway

We aim to investigate the function and mechanism of GanDouLing combinated with Penicillamine on cerebrovascular injury in Wilson’s disease (WD). ELISA was performed to analyze the expression of vascular injury factors. Pathological changes of cerebral vessels were observed by HE stain. Immunohistochemistry assays were performed to analyze the expression of ICAM-1, VCAM-1, and GRP78. Western blotting was measured to analyze the expression of caspase-3, caspase-12, PERK, eIF2α, and CHOP. Apoptosis was detected with TUNEL assay. The expression of vascular injury factors and ICAM-1, VCAM-1 was significantly increased by WD and markedly decreased in GanDouLing-Penicillamine group. The expression of caspase-3, caspase-12, PERK, eIF2α, and CHOP were obviously expressed in Wilson group, GanDouLing-Penicillamine suppressed apoptosis and endoplasmic reticulum (ER) stress. Our findings suggested that GanDouLing-Penicillamine improved cerebrovascular injury through PERK/eIF2α/CHOP ER stress pathway in the mouse model of WD.

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