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      Ulinastatin Inhibits the Proliferation, Invasion and Phenotypic Switching of PDGF-BB-Induced VSMCs via Akt/eNOS/NO/cGMP Signaling Pathway

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          Abstract

          Background

          Atherosclerosis is a chronic inflammatory disease responsible for thrombosis, blood supply disorders, myocardial infarction and strokes, eventually leading to increased deaths and reduced quality of life. As inflammation plays a vital role in the development of this disease, the present study aims to investigate whether urinary trypsin inhibitor (UTI) with anti-inflammatory property can inhibit the proliferation, invasion and phenotypic switching of PDGF-BB-induced vascular smooth muscle cells (VSMCs) and probe its potential mechanism.

          Methods

          Western blot was used to detect the expressions of the proteins related to the Akt/eNOS/NO/cGMP signaling pathway, phenotypic switching and proliferation. CCK-8 assay and EdU staining were used to detect cell proliferation of VSMCs. Transwell and wound healing assays were respectively conducted to measure the invasion and migration of VSMCs. The concentration of NO was evaluated by NO detection kit. ELISA assay analyzed the expression of cyclic GMP (cGMP).

          Results

          The expressions of p-Akt and p-eNOS were elevated by UTI treatment. Furthermore, UTI inhibited the proliferation, migration and invasion of VSMCs. UTI also increased the expressions of proteins related to phenotypic switching. The amount of NO and expression of cGMP were both elevated under UTI treatment.

          Conclusion

          UTI inhibits the proliferation, invasion and phenotypic switching of PDGF-BB-induced VSMCs via Akt/eNOS/NO/cGMP signaling pathway, which might provide a theoretical basis for the UTI treatment of atherosclerosis.

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          Most cited references 36

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          Lessons From Sudden Coronary Death

          Arteriosclerosis, Thrombosis, and Vascular Biology, 20(5), 1262-1275
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            Strategies to increase nitric oxide signalling in cardiovascular disease.

            Nitric oxide (NO) is a key signalling molecule in the cardiovascular, immune and central nervous systems, and crucial steps in the regulation of NO bioavailability in health and disease are well characterized. Although early approaches to therapeutically modulate NO bioavailability failed in clinical trials, an enhanced understanding of fundamental subcellular signalling has enabled a range of novel therapeutic approaches to be identified. These include the identification of: new pathways for enhancing NO synthase activity; ways to amplify the nitrate-nitrite-NO pathway; novel classes of NO-donating drugs; drugs that limit NO metabolism through effects on reactive oxygen species; and ways to modulate downstream phosphodiesterases and soluble guanylyl cyclases. In this Review, we discuss these latest developments, with a focus on cardiovascular disease.
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              Vascular smooth muscle cell in atherosclerosis.

              Vascular smooth muscle cells (VSMCs) exhibit phenotypic and functional plasticity in order to respond to vascular injury. In case of the vessel damage, VSMCs are able to switch from the quiescent 'contractile' phenotype to the 'proinflammatory' phenotype. This change is accompanied by decrease in expression of smooth muscle (SM)-specific markers responsible for SM contraction and production of proinflammatory mediators that modulate induction of proliferation and chemotaxis. Indeed, activated VSMCs could efficiently proliferate and migrate contributing to the vascular wall repair. However, in chronic inflammation that occurs in atherosclerosis, arterial VSMCs become aberrantly regulated and this leads to increased VSMC dedifferentiation and extracellular matrix formation in plaque areas. Proatherosclerotic switch in VSMC phenotype is a complex and multistep mechanism that may be induced by a variety of proinflammatory stimuli and hemodynamic alterations. Disturbances in hemodynamic forces could initiate the proinflammatory switch in VSMC phenotype even in pre-clinical stages of atherosclerosis. Proinflammatory signals play a crucial role in further dedifferentiation of VSMCs in affected vessels and propagation of pathological vascular remodelling.
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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
                14 December 2020
                2020
                : 14
                : 5505-5514
                Affiliations
                [1 ]Department of Cardiology, Guangdong Cardiovascular Institute, Guangdong Provincial Key Laboratory of Coronary Heart Disease Prevention, Guangdong Academy of Medical Sciences , Guangzhou, Guangdong 510055, People’s Republic of China
                Author notes
                Correspondence: Cheng Huang Guangdong Cardiovascular Institute, Guangdong Provincial Key Laboratory of Coronary Heart Disease Prevention, Guangdong Academy of Medical Sciences , Dongchuan Road, 96#, Guangzhou, Guangdong510055, People’s Republic of China Email huangcheng099@126.com
                Article
                275488
                10.2147/DDDT.S275488
                7753898
                © 2020 Huang 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: 5, References: 36, Pages: 10
                Funding
                Funded by: National Natural Science Foundation of China, open-funder-registry 10.13039/501100001809;
                Funded by: Medical Research Fund of Guangdong Province;
                National Natural Science Foundation of China (81300230). Medical Research Fund of Guangdong Province (2019612114114896).
                Categories
                Original Research

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