Abstract 143: Endoplasmic Reticulum Stress Impairs Vascular Function Through Enhanced Nadph Oxidase Activity and Reduction in Enos Activity

Hypertension ◽  
2012 ◽  
Vol 60 (suppl_1) ◽  
Author(s):  
Maria Galan ◽  
Modar Kassan ◽  
Mohamed Trebak ◽  
Khalid Matrougui
Keyword(s):  
Endoplasmic Reticulum ◽  
Nadph Oxidase ◽  
Er Stress ◽  
P38 Mapk ◽  
Vascular Function ◽  
Oxidase Activity ◽  
Mrna Levels ◽  
Stress Induction ◽  
Nadph Oxidase Activity ◽  
Enos Phosphorylation

Cardiovascular diseases are associated with the induction of endoplasmic reticulum (ER) stress. The induction of ER stress in C57BL/6J and p47phox-/- mice, by the injection of tunicamycin, greatly impaired vascular endothelium-dependent relaxation in C57BL/6J than in p47phox-/- mice. To determine the mechanism by which ER stress impairs endothelium function, we incubated mice primary endothelial cells from coronary arteries (ECs) with tunicamycin (1 μg/mL) for 6 h in the presence or absence of two ER stress inhibitors (Tudca, 500 μg/mL and PBA, 10 mM). Tunicamycin increased the phosphorylation of PERK and eIF2alpha, the expression of CHOP, ATF6 and Bip, Nox2/Nox4 mRNA levels, NADPH oxidase activity and superoxide anion levels. In addition, phosphorylated eNOS and nitrites levels were reduced with tunicamycin. All these events were prevented, at least partially, with the inhibition of ER stress. Tunicamycin treatment or the transfection of ECs with plasmids that express ATF6 or CHOP reduced the luciferase activity of a reporter plasmid containing the eNOS promoter. The ER stress induction reduced ERK1/2 phosphorylation and increased p38 MAPK phosphorylation. The inhibition of p38 MAPK restored the eNOS promoter activity and the eNOS phosphorylation, and reduced Bip but did not affect to ATF6 or CHOP expression. Conclusion: ER stress induction impairs endothelial cell eNOS-dependent activity by oxidative stress and p38 MAPK-dependent mechanisms.

scholarly journals RAC2-P38 MAPK-dependent NADPH oxidase activity is associated with the resistance of quiescent cells to ionizing radiation

Cell Cycle ◽  
2016 ◽  
Vol 16 (1) ◽  
pp. 113-122 ◽  
Author(s):  
Hailong Pei ◽  
Jian Zhang ◽  
Jing Nie ◽  
Nan Ding ◽  
Wentao Hu ◽  
...  
Keyword(s):  
Ionizing Radiation ◽  
Nadph Oxidase ◽  
P38 Mapk ◽  
Oxidase Activity ◽  
Nadph Oxidase Activity ◽  
Quiescent Cells

Abstract 211: Aldehyde Dehydrogenase 2 Deficiency Aggravates Cardiac Dysfunction Elicited by Endoplasmic Reticulum Stress Induction

2012 ◽  
Vol 111 (suppl_1) ◽  
Author(s):  
Aijun Sun ◽  
Jianquan Liao ◽  
Xieye Qing ◽  
Xueting Jin ◽  
Toyoshi Isse ◽  
...  
Keyword(s):  
Endoplasmic Reticulum ◽  
Nadph Oxidase ◽  
Er Stress ◽  
Aldehyde Dehydrogenase ◽  
Cardiac Dysfunction ◽  
Aldehyde Dehydrogenase 2 ◽  
Stress Induction ◽  
Protein Levels ◽  
Stress Markers

Mitochondrial aldehyde dehydrogenase-2 (ALDH2) has been characterized as an important mediator of endogenous cytoprotection in the heart. This study was designed to examine the role of aldehyde dehydrogenase-2 knockout (KO) in the pathogenesis of heart underwent endoplasmic reticulum (ER) stress induction. Wild-type (WT) and ALDH2 KO mice were subjected to tunicamycin challenge and echocardiographic examination was performed. Protein levels of GRP78, p-eIF2α, CHOP, phosphorylation of Akt, p47phox NADPH oxidase, and 4-hydroxynonenal were determined by Western blot analysis. Cytotoxicity and apoptosis were estimated by MTT assay and caspase-3 activity respectively. ALDH2 deficiency exacerbated cardiac dysfunction and increased the protein levels of ER stress markers after ER stress induction characterized by the changes of ejection fraction and fractional shorting, when compared with WT mice. In vitro, tunicamycin significantly increased in the levels of GRP78, p-eIF2, CHOP and p47phox NADPH oxidase, which was exacerbated by ALDH2 knockdown and abolished by ALDH2 overexpression. Overexpression of ALDH2 abrogated tunicamycin-induced dephosphorylation of Akt. Inhibition of PI3-K with LY294002 did not negatively affect the inhibition of ER stress markers conferred by ALDH2, but reversed the anti-apoptotic role of ALDH2, which may be associated with p47phox NADPH oxidase. These results suggest that ALDH2 was implicated in the regulation of ER stress and ER stress-induced apoptosis. The protective role of ALDH2 against cell death induced by ER stress was probably mediated by Akt signaling via p47phox NADPH oxidase. These findings indicate a critical role of ALDH2 in the pathogenesis of ER stress in heart disease.

Abstract P063: Pitavastatin Has Antihypertensive and Renoprotective Effects With Upregulation of No System and Down-regulation of Oxidative Stress in the Kidney of Spontaneously Hypertensive Rats

Hypertension ◽  
2015 ◽  
Vol 66 (suppl_1) ◽  
Author(s):  
Gaizun Hu ◽  
Osamu Ito ◽  
Rong Rong ◽  
Bin Xu ◽  
Akihiro Sakuyama ◽  
...  
Keyword(s):  
Oxidative Stress ◽  
Blood Pressure ◽  
Nadph Oxidase ◽  
Oxidase Activity ◽  
Active Form ◽  
Thiobarbituric Acid ◽  
Down Regulation ◽  
Spontaneously Hypertensive ◽  
Nadph Oxidase Activity ◽  
Enos Phosphorylation

Clinical trials have demonstrated renoprotective effects of atorvastatin (ATV) and pitavastatin (PTV), which belong to the strong statins, are more potent than other statins. We reported previously that ATV attenuated the development of hypertension in SHR with increasing the endothelial and neuronal NO synthases (eNOS, nNOS) expressions in the kidney, whereas ATV inhibited the eNOS phosphorylation at serin1177 (J Hypertes 28: 2278-2288, 2010). To clarify the mechanisms of renoprotective effects of PTV, the present study examined the effects of PTV on blood pressure, renal functions, NOS and oxidative stress in the kidney of SHR. Five-week-old, male SHR were given orally PTV (2mg/kg/day) or vehicle for 8 weeks. The systolic blood pressure (SBP) was measured. The NOS expression and eNOS phosphorylation were analyzed by Western blot. The NADPH oxidase activity was measured by the lucigenin-enhanced chemiluminescence method. PTV attenuated the progression of hypertension (220 ± 8 vs. 177± 4 mmHg, P<0.01) and albuminuria (684 ± 66 vs. 398 ± 42 mg/day, P<0.01) without changing plasma total cholesterol or creatinine. PTV increased the eNOS and nNOS expressions in the outer and inner medulla of the kidney (eNOS; by 182% and 186%, nNOS; by 315% and 194%, P<0.01). PTV significantly stimulated the eNOS phosphorylation at serin1177 in the inner medulla and inhibited the eNOS phosphorylation at threonine495 in the outer and inner medulla. PTV decreased hydrogen peroxide (13.4 ± 2.1 vs. 6.1 ± 1.2 nmol/day, P<0.05) and thiobarbituric acid reactive substances (TBARS) (236.6 ± 12.4 vs. 198.3 ± 10.6 nmol/day, P<0.05) in the urine and the NADPH oxidase activity (42681± 2515 vs. 32381 ± 1995 c.p.m/mg protein, P<0.01) in the renal cortex. These results indicate that PTV attenuates the development of hypertension and albuminuria in SHR with increasing the eNOS and nNOS expressions, changing the eNOS phosphorylation to an active form and mitigating oxidative stress in the kidney. The antihypertensive and renoprotective effects of PTV may be mediated in part by an upregulation of NO system and down-regulation of oxidative stress in the kidney.

Mitochondria-targeted peptide SS-31 attenuates renal injury via an antioxidant effect in diabetic nephropathy

2016 ◽  
Vol 310 (6) ◽  
pp. F547-F559 ◽  
Author(s):  
Yanjuan Hou ◽  
Shuangcheng Li ◽  
Ming Wu ◽  
Jinying Wei ◽  
Yunzhuo Ren ◽  
...  
Keyword(s):  
Diabetic Nephropathy ◽  
Nadph Oxidase ◽  
P38 Mapk ◽  
Renal Injury ◽  
Oxidase Activity ◽  
Transforming Growth Factor ◽  
Ros Generation ◽  
Diabetic Mice ◽  
Nadph Oxidase Activity ◽  
Tgf Β1

Oxidative stress is implicated in the pathogenesis of diabetic kidney injury. SS-31 is a mitochondria-targeted tetrapeptide that can scavenge reactive oxygen species (ROS). Here, we investigated the effect and molecular mechanism of mitochondria-targeted antioxidant peptide SS-31 on injuries in diabetic kidneys and mouse mesangial cells (MMCs) exposed to high-glucose (HG) ambience. CD-1 mice underwent uninephrectomy and streptozotocin treatment prior to receiving daily intraperitoneal injection of SS-31 for 8 wk. The diabetic mice treated with SS-31 had alleviated proteinuria, urinary 8-hydroxy-2-deoxyguanosine level, glomerular hypertrophy, and accumulation of renal fibronectin and collagen IV. SS-31 attenuated renal cell apoptosis and expression of Bax and reversed the expression of Bcl-2 in diabetic mice kidneys. Furthermore, SS-31 inhibited expression of transforming-growth factor (TGF)-β1, Nox4, and thioredoxin-interacting protein (TXNIP), as well as activation of p38 MAPK and CREB and NADPH oxidase activity in diabetic kidneys. In vitro experiments using MMCs revealed that SS-31 inhibited HG-mediated ROS generation, apoptosis, expression of cleaved caspase-3, Bax/Bcl-2 ratio, and cytochrome c (cyt c) release from mitochondria. SS-31 normalized mitochondrial potential (ΔΨm) and ATP alterations, and inhibited the expression of TGF-β1, Nox4, and TXNIP, as well as activation of p38 MAPK and CREB and NADPH oxidase activity in MMCs under HG conditions. SS-31 treatment also could reverse the reduction of thioredoxin (TRX) biologic activity and upregulate expression of thioredoxin 2 (TRX2) in MMCs under HG conditions. In conclusion, this study demonstrates a protective effect of SS-31 against HG-induced renal injury via an antioxidant mechanism in diabetic nephropathy.

scholarly journals Effect of thimerosal on thyroid hormones metabolism in rats

2017 ◽  
Vol 6 (8) ◽  
pp. 741-747 ◽  
Author(s):  
Thiago U Pantaleão ◽  
Andrea C F Ferreira ◽  
Maria C S Santos ◽  
Álvaro S P Figueiredo ◽  
Ruy A N Louzada ◽  
...  
Keyword(s):  
Nadph Oxidase ◽  
Thyroid Hormones ◽  
Oxidase Activity ◽  
Inhibitory Effect ◽  
Female Rats ◽  
Mrna Levels ◽  
Nadph Oxidase Activity ◽  
Amplex Red ◽  
Hrp Method ◽  
Peripheral Metabolism

Mercury seems to exert an inhibitory effect on deiodinases, but there are few studies using Thimerosal (TM) as the mercury source. We aimed to elucidate the effect of TM on thyroid hormones peripheral metabolism. Adult Wistar female rats received 0.25 µg or 250 µg TM/100 g BW, IM, twice a week, for a month. We evaluated serum total T3 and T4, D1 activity using 125I-rT3 as tracer, and D2 activity using 125I-T4. NADPH oxidase activity was measured by Amplex-red/HRP method and mRNA levels by real time PCR. Serum T4 was increased and T3 decreased by the greatest dose of TM. Even though D1 activity in pituitary and kidney was reduced by the highest dose of TM, hepatic D1 activity and D1 mRNA levels remained unchanged. D2 activity was also significantly decreased by the highest dose of TM in all CNS samples tested, except cerebellum, but D2 mRNA was unaltered. mRNA levels of the tested NADPH oxidases were not affected by TM and NADPH oxidase activity was either unaltered or decreased. Our results indicate that TM might directly interact with deiodinases, inhibiting their activity probably by binding to their selenium catalytic site, without changes in enzyme expression.

Abstract 33: Endoplasmic Reticulum Stress and Vascular Dysfunction in Hypertension

2012 ◽  
Vol 111 (suppl_1) ◽  
Author(s):  
Modar Kassan ◽  
Maria Galan ◽  
Megan Partyka ◽  
Daniel Henrion ◽  
Mohamed Trebak ◽  
...  
Keyword(s):  
Endoplasmic Reticulum ◽  
Er Stress ◽  
Vascular Function ◽  
Vascular Dysfunction ◽  
Ang Ii ◽  
Resistance Arteries ◽  
Cardiac Damage ◽  
Stress Markers ◽  
Enos Phosphorylation ◽  
Dependent Mechanism

Objective: Cardiac damage and vascular dysfunction are major causes of morbidity and mortality in hypertension. In this study, we explored the beneficial therapeutic effect of endoplasmic reticulum (ER) stress inhibition on cardiac damage and vascular dysfunction in hypertension. Methods & results: Mice were infused with angiotensin II (Ang-II, 400 ng/kg/min) with or without ER stress inhibitors (Tudca and PBA) for two weeks. Mice infused with Ang-II displayed an increase in blood pressure, cardiac hypertrophy and fibrosis associated with enhanced collagen-I content, TGFβ1 activity, and ER stress markers, which were blunted after ER stress inhibition. Hypertension induced ER stress in aorta and mesenteric resistance arteries (MRA), enhanced TGFβ1 activity in aorta but not in MRA, and reduced eNOS phosphorylation and endothelium-dependent relaxation (EDR) in aorta and MRA. The inhibition of ER stress significantly reduced TGFβ1 activity, enhanced eNOS phosphorylation and improved EDR. The inhibition of TGFβ1 pathway improved EDR in aorta but not in MRA, while the reduction in ROS levels ameliorated EDR in MRA only. Infusion of tunicamycin in control mice induced ER stress in aorta and MRA, and reduced EDR by a TGFβ1-dependent mechanism in aorta and ROS-dependent mechanism in MRA. Conclusion: ER stress inhibition reduces cardiac damage and improves vascular function in hypertension. Therefore ER stress could be a potential target for cardiovascular diseases.

scholarly journals NADPH oxidase activity is required for ER stress survival in plants

2018 ◽  
Vol 96 (6) ◽  
pp. 1106-1120 ◽  
Author(s):  
Evan Angelos ◽  
Federica Brandizzi
Keyword(s):  
Nadph Oxidase ◽  
Er Stress ◽  
Oxidase Activity ◽  
Nadph Oxidase Activity ◽  
Stress Survival

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.

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