Effects of oligomeric grape seed proanthocyanidins on L-
NAME-
induced hypertension in pregnant mice: Role of oxidative stress and endothelial dysfunction

Cardiovascular diseases (CVDs) are the most common cause of morbidity and mortality worldwide. The potential benefits of natural antioxidants derived from supplemental nutrients against CVDs are well known. Remarkably, natural antioxidants exert cardioprotective effects by reducing oxidative stress, increasing vasodilation, and normalizing endothelial dysfunction. Recently, considerable evidence has highlighted an important role played by the synergistic interaction between endothelial nitric oxide synthase (eNOS) and sirtuin 1 (SIRT1) in the maintenance of endothelial function. To provide a new perspective on the role of natural antioxidants against CVDs, we focused on microRNAs (miRNAs), which are important posttranscriptional modulators in human diseases. Several miRNAs are regulated via the consumption of natural antioxidants and are related to the regulation of oxidative stress by targeting eNOS and/or SIRT1. In this review, we have discussed the specific molecular regulation of eNOS/SIRT1-related endothelial dysfunction and its contribution to CVD pathologies; furthermore, we selected nine different miRNAs that target the expression of eNOS and SIRT1 in CVDs. Additionally, we have summarized the alteration of miRNA expression and regulation of activities of miRNA through natural antioxidant consumption.

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The Role of the FOXO1/β2-AR/p-NF-κB p65 Pathway in the Development of Endometrial Stromal Cells in Pregnant Mice under Restraint Stress

International Journal of Molecular Sciences ◽

10.3390/ijms22031478 ◽

2021 ◽

Vol 22 (3) ◽

pp. 1478

Author(s):

Jiayin Lu ◽

Yaoxing Chen ◽

Zixu Wang ◽

Jing Cao ◽

Yulan Dong

Keyword(s):

Oxidative Stress ◽

Stromal Cells ◽

Restraint Stress ◽

Target Genes ◽

Mrna Levels ◽

Endometrial Stromal Cells ◽

Protein Levels ◽

Pregnant Mice

Restraint stress causes various maternal diseases during pregnancy. β2-Adrenergic receptor (β2-AR) and Forkhead transcription factor class O 1 (FOXO1) are critical factors not only in stress, but also in reproduction. However, the role of FOXO1 in restraint stress, causing changes in the β2-AR pathway in pregnant mice, has been unclear. The aim of this research was to investigate the β2-AR pathway of restraint stress and its impact on the oxidative stress of the maternal uterus. In the study, maternal mice were treated with restraint stress by being restrained in a transparent and ventilated device before sacrifice on Pregnancy Day 5 (P5), Pregnancy Day 10 (P10), Pregnancy Day 15 (P15), and Pregnancy Day 20 (P20) as well as on Non-Pregnancy Day 5 (NP5). Restraint stress augmented blood corticosterone (CORT), norepinephrine (NE), and blood glucose levels, while oestradiol (E2) levels decreased. Moreover, restraint stress increased the mRNA levels of the FOXO family, β2-AR, and even the protein levels of FOXO1 and β2-AR in the uterus and ovaries. Furthermore, restraint stress increased uterine oxidative stress level. In vitro, the protein levels of FOXO1 were also obviously increased when β2-AR was activated in endometrial stromal cells (ESCs). In addition, phosphorylated-nuclear factor kappa-B p65 (p-NF-κB p65) and its target genes decreased significantly when FOXO1 was inhibited. Overall, it can be said that the β2-AR/FOXO1/p-NF-κB p65 pathway was activated when pregnant mice were under restraint stress. This study provides a scientific basis for the origin of psychological stress in pregnant women.

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The role of diabetes in the onset and development of endothelial dysfunction

Problems of Endocrinology ◽

10.14341/probl12212 ◽

2020 ◽

Vol 66 (1) ◽

pp. 47-55

Author(s):

Era B. Popyhova ◽

Tatiana V. Stepanova ◽

Dar’ya D. Lagutina ◽

Tatiana S. Kiriiazi ◽

Alexey N. Ivanov

Keyword(s):

Oxidative Stress ◽

Endothelial Dysfunction ◽

Critical Role ◽

Vascular Complications ◽

Glycation End Products ◽

Smooth Muscle Cell Migration ◽

Basic Functions ◽

Cell Migration And Proliferation ◽

Radical Processes

The vascular endothelium performs many functions. It is a key regulator of vascular homeostasis, maintains a balance between vasodilation and vasoconstriction, inhibition and stimulation of smooth muscle cell migration and proliferation, fibrinolysis and thrombosis, and is involved to regulation of platelet adhesion and aggregation. Endothelial dysfunction (ED) plays the critical role in pathogenesis of diabetes mellitus (DM) vascular complications. The purpose of this review was to consider the mechanisms leading to the occurrence of ED in DM. The paper discusses current literature data concerning the role of hyperglycemia, oxidative stress, advanced glycation end products in endothelial alteration. A separate section is devoted to the particularities of the functioning of the antioxidant system and their significance in the development of ED in DM. The analysis of the literature allows to conclude that pathological activation of glucose utilization pathways causes damage of endothelial cells, which is accompanied by disorders of all their basic functions. Metabolic disorders in DM cause a pronounced imbalance of free radical processes and antioxidant defense, accompanied by oxidative stress of endotheliocytes, which contributes to the progression of ED and the development of vascular complications. Many aspects of multicomponent regulatory reactions in the pathogenesis of the development of ED in DM have not been sufficiently studied.

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Omega 3 Polyunsaturated Fatty Acids Improve Endothelial Dysfunction in Chronic Renal Failure: Role of eNOS Activation and of Oxidative Stress

Nutrients ◽

10.3390/nu9080895 ◽

2017 ◽

Vol 9 (8) ◽

pp. 895 ◽

Cited By ~ 13

Author(s):

Michela Zanetti ◽

Gianluca Gortan Cappellari ◽

Davide Barbetta ◽

Annamaria Semolic ◽

Rocco Barazzoni

Keyword(s):

Oxidative Stress ◽

Fatty Acids ◽

Renal Failure ◽

Chronic Renal Failure ◽

Endothelial Dysfunction ◽

Polyunsaturated Fatty Acids ◽

Omega 3

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Abstract 357: Hepatic ERK2 Suppresses Endoplasmic Reticulum Stress, Leading to Protection from Oxidative Stress and Endothelial Dysfunction

Arteriosclerosis Thrombosis and Vascular Biology ◽

10.1161/atvb.33.suppl_1.a357 ◽

2013 ◽

Vol 33 (suppl_1) ◽

Author(s):

Takehiko Kujiraoka ◽

Yasushi Satoh ◽

Makoto Ayaori ◽

Yasunaga Shiraishi ◽

Yuko Arai-Nakaya ◽

...

Keyword(s):

Oxidative Stress ◽

Insulin Resistance ◽

Endoplasmic Reticulum ◽

Fatty Acid ◽

Endothelial Dysfunction ◽

Er Stress ◽

Vascular Complications ◽

Metabolic Remodeling ◽

And Oxidative Stress

Background Insulin signaling comprises 2 major cascades, the IRS/PI3K/Akt and Ras/Raf/MEK/ERK pathways. Many studies on the tissue-specific effects of the former pathway had been conducted, however, the role of the latter cascade in tissue-specific insulin resistance had not been investigated. High glucose/fatty acid toxicity, inflammation and oxidative stress, all of which are associated with insulin resistance, can activate ERK. Liver plays a central role of metabolism and hepatosteatosis (HST) is associated with vascular diseases. The aim of this study is to elucidate the role of hepatic ERK2 in HST, metabolic remodeling and endothelial dysfunction. Methods Serum biomarkers of vascular complications in human were compared between subjects with and without HST diagnosed by echography for regular medical checkup. Next, we created liver-specific ERK2 knockout mice (LE2KO) and fed them with a high-fat/high-sucrose diet (HFHSD) for 20 weeks. The histological analysis, the expression of hepatic sarco/endoplasmic reticulum (ER) Ca 2+ -ATPase 2 (SERCA2) and glucose-tolerance/insulin-sensitivity (GT/IS) were tested. Vascular superoxide production and endothelial function were evaluated with dihydroethidium staining and isometric tension measurement of aorta. Results The presence of HST significantly increased HOMA-IR, an indicator of insulin resistance or atherosclerotic index in human. HFHSD-fed LE2KO revealed a marked exacerbation in HST and metabolic remodeling represented by the impairment of GT/IS, elevated serum free fatty acid and hyperhomocysteinemia without changes in body weight, blood pressure and serum cholesterol/triglyceride levels. In the HFHSD-fed LE2KO, mRNA and protein expressions of hepatic SERCA2 were significantly decreased, which resulted in hepatic ER stress. Induction of vascular superoxide production and remarkable endothelial dysfunction were also observed in them. Conclusions Hepatic ERK2 revealed the suppression of hepatic ER stress and HST in vivo , which resulted in protection from vascular oxidative stress and endothelial dysfunction. HST with hepatic ER stress can be a prominent risk of vascular complications by metabolic remodeling and oxidative stress in obese-related diseases.

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Abstract 277: Elevated C-Reactive Protein Contributes to Preeclampsia via Kinin Signaling Pathways

Hypertension ◽

10.1161/hyp.62.suppl_1.a277 ◽

2013 ◽

Vol 62 (suppl_1) ◽

Author(s):

Nicholas Parchim ◽

Wei Wang ◽

Takayuki Iriyama ◽

Chen Liu ◽

Athar H Siddiqui ◽

...

Keyword(s):

Acute Phase Reactant ◽

Receptor Activation ◽

C Reactive Protein ◽

Direct Role ◽

Human Trophoblast ◽

Reactive Protein ◽

Induced Hypertension ◽

Pregnant Mice

Preeclampsia (PE) is a serious pregnancy disease characterized by hypertension and proteinuria. Despite intensive research efforts, the underlying cause of PE remains a mystery. PE is, however, associated with abnormalities of the immune system. Here we report that the levels of C-reactive protein (CRP), an important acute phase reactant, were significantly elevated in the plasma of human with PE at the third trimester. Next, we found that CRP protein levels in the placentas of PE patients were also significantly increased compared to controls. In an effort to determine the exact role of elevated CRP in PE, we infused CRP into pregnant mice. We found that injection of CRP into pregnant mice induced hypertension (170 mmHg mean systolic vs. 125 mmHg mean systolic control; p<0.05) and proteinuria (25 mg/ug vs 12 mg/ug vehicle; p<0.05), indicating the direct role of CRP in PE. CRP is known to bind with phosphocholine on damaged cell membranes. Recent studies identified that neurokinin B (NKB), a placental enriched neuropeptide and known pathogenic molecule for PE, is phosphocholinated. This posttranslational modification increases its stability and enhances NKB-mediated receptor activation. These findings raise an intriguing hypothesis that CRP may bind with NKB coupled to NK3R activation and contribute to PE. To test this hypothesis, we conducted a pulldown assay, and we found that CRP bound with NKB. Next, using a cellular invasion assay, we revealed that CRP decreased invasion of human trophoblast cells (0.7 to 0.07 invasion index, p<0.05), while treatment with an NK3R selective antagonist, SB222200, ameliorated this shallow invasion. Finally, we provided in vivo evidence that inhibition of NK3R by SB222200 or knockdown of NK3R by specific siRNA in a potent nanoparticle delivery system significantly reduced CRP-induced hypertension and proteinuria in pregnant mice (170 mmHg mean systolic CRP-injected vs. 130 mmHg mean systolic siRNA NK3R; p<0.05 and proteinuria 25 mg/ug vs. 15 mg/ug; p<0.05). Overall, our findings demonstrate that elevated CRP contributes to PE and NKB/NK3R is a novel mechanism underlying CRP-mediated shallow invasion and disease development. These studies suggest novel pathogenic biomarkers and innovative therapeutic targets for PE.

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Abstract 45: Pathological Role of LIGHT, a New TNF-alpha Superfamily Member, in Preeclampsia via Activation of HVEM and LTβR

Hypertension ◽

10.1161/hyp.60.suppl_1.a45 ◽

2012 ◽

Vol 60 (suppl_1) ◽

Author(s):

Wei Wang ◽

Roxanna A Irani ◽

Haixiong Liu ◽

Yujing Zhang ◽

Lijian Tao ◽

...

Keyword(s):

Neutralizing Antibodies ◽

Kidney Injury ◽

Current Treatment ◽

Hypertensive Disorder ◽

Mortality And Morbidity ◽

Endothelium Dysfunction ◽

Induced Hypertension ◽

Pregnant Mice ◽

Role Of Light

Preeclampsia (PE) is a life-threatening hypertensive disorder of pregnancy that is a leading cause of maternal and neonatal mortality and morbidity. The current treatment for PE is limited because underlying pathophysiologic mechanisms remain undefined. PE is, however, recognized as an autoimmune disease, which is associated with a series of inflammatory cytokines. Using sensitive ELISA arrays, we discovered a pronounced inflammatory response was stimulated in circulation of PE patients, including elevated levels of LIGHT, a novel TNF superfamily member, which is involved in pathogenesis of series of autoimmune diseases. Next, we confirmed that LIGHT is significantly increased in the circulation and placenta women with PE. In order to determine the role of LIGHT in pathophyisology of PE, we injected recombinant LIGHT into pregnant mice and non-pregnant mice. We demonstrated that LIGHT directly induces major clinical PE features including hypertension (161±3mmHg vs. control 122±3mmHg, p<0.05) and proteinuria (57±2.7μg/mg vs. control 22±2.5μg albumin/mg creatinine, p<0.05) in the pregnant mice. In contrast,LIGHT only induced hypertension (149±2mmHg vs. control 122±8mmHg, p<0.05) but not proteinuria in non-pregnant mice, indicating LIGHT has a previously unrecognized role in pathophysiology of PE and its detrimental effects on kidney injury is pregnancy-dependent. Mechanistically, using neutralizing antibodies for LIGHT receptors, we found that LIGHT transmembrane receptors, HVEM and LTβR, are required for LIGHT-induced hypertension and proteinuria in the pregnant mice by inducing sFlt-1 production, impaired placental angiogenesis and endothelium dysfunction in pregnant mice. Overall, our studies provide both human and mouse evidence that elevated LIGHT contributes to pathophysiology of PE via both HVEM and LTβR signaling and immediately suggest a novel therapeutic possibility.

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