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      Loxoprofen Sodium Alleviates Oxidative Stress and Apoptosis Induced by Angiotensin II in Human Umbilical Vein Endothelial Cells (HUVECs)

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          Abstract

          Background and Purpose

          Endothelium exerts an important role in releasing vasoactive substances, maintaining the blood flow, regulating the growth of vessels, moderating the process of coagulation, and the balance of fibrinolytic system, the dysfunction of which is reported to result in arterial stiffness. The present study aimed to investigate the effects of loxoprofen sodium against HUVECs injury induced by angiotensin II.

          Methods

          The injury model on HUVECs was established through incubation with angiotensin II. The expression levels of AT2R, NOX-4, Bax, Bcl-2, and caspase-3 were evaluated using qRT-PCR and Western Blot. DCFH-DA assay was used to detect the production of ROS and ELISA assay was used to evaluate the level of reduced glutathione. Mitochondrial membrane potential (MMP) was measured using dihydrorhodamine 123 assay. MTT and LDH assays were utilized to determine the proliferation ability of HUVECs. The apoptosis rate of HUVECs was evaluated using flow cytometry.

          Results

          Loxoprofen sodium suppressed endothelial AT2R elevation by angiotensin II. Loxoprofen ameliorated Angiotensin II–induced production of ROS, reduced GSH, and NOX-2 and NOX-4 expression. Furthermore, Loxoprofen mitigated Angiotensin II, reduced mitochondrial membrane potential and improved cell viability, and suppressed LDH release by angiotensin II. Importantly, loxoprofen showed a beneficial role in protecting endothelial apoptosis by mitigating apoptotic machinery including the balanced expression of Bax, Bcl-2, and caspase-3 cleavage.

          Conclusion

          Loxoprofen sodium might alleviate the high ROS levels and apoptosis induced by angiotensin II in HUVECs.

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          Most cited references 43

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          Molecular mechanisms of angiotensin II-mediated mitochondrial dysfunction: linking mitochondrial oxidative damage and vascular endothelial dysfunction.

          Mitochondrial dysfunction is a prominent feature of most cardiovascular diseases. Angiotensin (Ang) II is an important stimulus for atherogenesis and hypertension; however, its effects on mitochondrial function remain unknown. We hypothesized that Ang II could induce mitochondrial oxidative damage that in turn might decrease endothelial nitric oxide (NO.) bioavailability and promote vascular oxidative stress. The effect of Ang II on mitochondrial ROS, mitochondrial respiration, membrane potential, glutathione, and endothelial NO. was studied in isolated mitochondria and intact bovine aortic endothelial cells using electron spin resonance, dihydroethidium high-performance liquid chromatography -based assay, Amplex Red and cationic dye fluorescence. Ang II significantly increased mitochondrial H2O2 production. This increase was blocked by preincubation of intact cells with apocynin (NADPH oxidase inhibitor), uric acid (scavenger of peroxynitrite), chelerythrine (protein kinase C inhibitor), N(G)-nitro-L-arginine methyl ester (nitric oxide synthase inhibitor), 5-hydroxydecanoate (mitochondrial ATP-sensitive potassium channels inhibitor), or glibenclamide. Depletion of p22(phox) subunit of NADPH oxidase with small interfering RNA also inhibited Ang II-mediated mitochondrial ROS production. Ang II depleted mitochondrial glutathione, increased state 4 and decreased state 3 respirations, and diminished mitochondrial respiratory control ratio. These responses were attenuated by apocynin, 5-hydroxydecanoate, and glibenclamide. In addition, 5-hydroxydecanoate prevented the Ang II-induced decrease in endothelial NO. and mitochondrial membrane potential. Therefore, Ang II induces mitochondrial dysfunction via a protein kinase C-dependent pathway by activating the endothelial cell NADPH oxidase and formation of peroxynitrite. Furthermore, mitochondrial dysfunction in response to Ang II modulates endothelial NO. and generation, which in turn has ramifications for development of endothelial dysfunction.
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            Pulmonary arterial hypertension: pathogenesis and clinical management

            Pulmonary hypertension is defined as a resting mean pulmonary artery pressure of 25 mm Hg or above. This review deals with pulmonary arterial hypertension (PAH), a type of pulmonary hypertension that primarily affects the pulmonary vasculature. In PAH, the pulmonary vasculature is dynamically obstructed by vasoconstriction, structurally obstructed by adverse vascular remodeling, and pathologically non-compliant as a result of vascular fibrosis and stiffening. Many cell types are abnormal in PAH, including vascular cells (endothelial cells, smooth muscle cells, and fibroblasts) and inflammatory cells. Progress has been made in identifying the causes of PAH and approving new drug therapies. A cancer-like increase in cell proliferation and resistance to apoptosis reflects acquired abnormalities of mitochondrial metabolism and dynamics. Mutations in the type II bone morphogenetic protein receptor ( BMPR2) gene dramatically increase the risk of developing heritable PAH. Epigenetic dysregulation of DNA methylation, histone acetylation, and microRNAs also contributes to disease pathogenesis. Aberrant bone morphogenetic protein signaling and epigenetic dysregulation in PAH promote cell proliferation in part through induction of a Warburg mitochondrial-metabolic state of uncoupled glycolysis. Complex changes in cytokines (interleukins and tumor necrosis factor), cellular immunity (T lymphocytes, natural killer cells, macrophages), and autoantibodies suggest that PAH is, in part, an autoimmune, inflammatory disease. Obstructive pulmonary vascular remodeling in PAH increases right ventricular afterload causing right ventricular hypertrophy. In some patients, maladaptive changes in the right ventricle, including ischemia and fibrosis, reduce right ventricular function and cause right ventricular failure. Patients with PAH have dyspnea, reduced exercise capacity, exertional syncope, and premature death from right ventricular failure. PAH targeted therapies (prostaglandins, phosphodiesterase-5 inhibitors, endothelin receptor antagonists, and soluble guanylate cyclase stimulators), used alone or in combination, improve functional capacity and hemodynamics and reduce hospital admissions. However, these vasodilators do not target key features of PAH pathogenesis and have not been shown to reduce mortality, which remains about 50% at five years. This review summarizes the epidemiology, pathogenesis, diagnosis, and treatment of PAH.
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              Endothelial NADPH oxidases: which NOX to target in vascular disease?

              NADPH oxidases (NOXs) are reactive oxygen species (ROS)-generating enzymes implicated in the pathophysiology of vascular diseases such as hypertension and stroke. Endothelial cells express four NOX isoforms including the superoxide-generating enzymes NOX1, NOX2, and NOX5 and the hydrogen peroxide-generating enzyme NOX4. Studies on arteries from patients with coronary artery disease, and in animals with experimentally induced hypertension, diabetes, or atherosclerosis, suggest that NOX1, NOX2, and NOX5 promote endothelial dysfunction, inflammation, and apoptosis in the vessel wall, whereas NOX4 is by contrast vasoprotective in increasing nitric oxide bioavailability and suppressing cell death pathways. Based on these findings and promising preclinical studies with the NOX1/NOX2 antagonist, apocynin, we suggest that the field is poised for clinical evaluation of NOX inhibitors as therapeutics for cardiovascular disease. Copyright © 2014 Elsevier Ltd. All rights reserved.
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                Author and article information

                Journal
                Drug Des Devel Ther
                Drug Des Devel Ther
                dddt
                dddt
                Drug Design, Development and Therapy
                Dove
                1177-8881
                18 November 2020
                2020
                : 14
                : 5087-5096
                Affiliations
                [1 ]Department of Cardiovascular Medicine Ward 2, Zibo Central Hospital , Zibo, Shandong 255020, People’s Republic of China
                [2 ]General Medicine Department of Zibo Central Hospital , Zibo, Shandong 255020, People’s Republic of China
                Author notes
                Correspondence: Shuo DongDepartment of Cardiovascular Medicine Ward 2, Zibo Central Hospital , No. 54, Gongqingtuan West Road, Zhangdian District, Zibo, Shandong255020, People’s Republic of ChinaTel/Fax +86-0533-3179175 Email shuodong601@163.com
                Article
                266175
                10.2147/DDDT.S266175
                7680688
                © 2020 Ji et al.

                This work is published and licensed by Dove Medical Press Limited. The full terms of this license are available at https://www.dovepress.com/terms.php and incorporate the Creative Commons Attribution – Non Commercial (unported, v3.0) License ( http://creativecommons.org/licenses/by-nc/3.0/). By accessing the work you hereby accept the Terms. Non-commercial uses of the work are permitted without any further permission from Dove Medical Press Limited, provided the work is properly attributed. For permission for commercial use of this work, please see paragraphs 4.2 and 5 of our Terms ( https://www.dovepress.com/terms.php).

                Page count
                Figures: 9, References: 44, Pages: 10
                Categories
                Original Research

                Pharmacology & Pharmaceutical medicine

                angiotensin ii, apoptosis, endothelial cells, ros

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