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      Low-dose doxycycline inhibits hydrogen peroxide-induced oxidative stress, MMP-2 up-regulation and contractile dysfunction in human saphenous vein grafts

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          Abstract

          Background: Cardiopulmonary bypass (CPB) applied during coronary artery bypass grafting (CABG), promotes inflammation, generation of reactive oxygen species (ROS) and up-regulation of matrix metalloproteinases (MMPs). All these complications may lead to contractile dysfunction, restenosis and early graft failure, restricting long-term efficacy of bypass grafts. Low-dose doxycycline is a potent MMP inhibitor and ROS scavenger. In this study, we aimed to investigate the effects of doxycycline on ROS generation, MMP regulation and contractile dysfunction induced by H 2O 2 in human saphenous vein (HSV) grafts.

          Methods: HSV grafts (n=7) were divided into four groups after removing endothelial layer by mechanical scratching and incubated with 10 µM H 2O 2 and/or 10 µM doxycycline for 16 hrs. Untreated segments served as control. Concentration–response curves to noradrenaline (NA), potassium chloride (KCl), serotonin (5-HT) and papaverine were performed. Superoxide anion and other ROS levels were determined by using lucigenin- and luminol-enhanced chemiluminescence assays, respectively. Expression/activity of gelatinases (MMP-2/MMP-9) was examined by gelatin zymography. MMP-13 expression was evaluated by immunostaining/immunoscoring.

          Results: H 2O 2 incubation increased superoxide anion and other ROS levels. Doxycycline prevented these increments. H 2O 2 suppressed contractile responses to NA, KCl and 5-HT. Doxycycline ameliorated contractions to NA and KCl but not to 5-HT. H 2O 2 or doxycycline did not altered relaxation to papaverine. MMP-2 and MMP-13 expression increased with H 2O 2, but doxycycline inhibited MMP-2 up-regulation/activation.

          Conclusion: Low-dose doxycycline may have beneficial effects on increased oxidative stress, MMP up-regulation/activation and contractile dysfunction in HSV grafts.

          Most cited references38

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          Dual role of matrix metalloproteinases (matrixins) in intimal thickening and atherosclerotic plaque rupture.

          Intimal thickening, the accumulation of cells and extracellular matrix within the inner vessel wall, is a physiological response to mechanical injury, increased wall stress, or chemical insult (e.g., atherosclerosis). If excessive, it can lead to the obstruction of blood flow and tissue ischemia. Together with expansive or constrictive remodeling, the extent of intimal expansion determines final lumen size and vessel wall thickness. Plaque rupture represents a failure of intimal remodeling, where the fibrous cap overlying an atheromatous core of lipid undergoes catastrophic mechanical breakdown. Plaque rupture promotes coronary thrombosis and myocardial infarction, the most prevalent cause of premature death in advanced societies. The matrix metalloproteinases (MMPs) can act together to degrade the major components of the vascular extracellular matrix. All cells present in the normal and diseased blood vessel wall upregulate and activate MMPs in a multistep fashion driven in part by soluble cytokines and cell-cell interactions. Activation of MMP proforms requires other MMPs or other classes of protease. MMP activation contributes to intimal growth and vessel wall remodeling in response to injury, most notably by promoting migration of vascular smooth muscle cells. A broader spectrum and/or higher level of MMP activation, especially associated with inflammation, could contribute to pathological matrix destruction and plaque rupture. Inhibiting the activity of specific MMPs or preventing their upregulation could ameliorate intimal thickening and prevent myocardial infarction.
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            Proteinase-activated receptors.

            Proteinase-activated receptors are a recently described, novel family of seven-transmembrane G-protein-coupled receptors. Rather then being stimulated through ligand receptor occupancy, activation is initiated by cleavage of the N terminus of the receptor by a serine protease resulting in the generation of a new tethered ligand that interacts with the receptor within extracellular loop-2. To date, four proteinase-activated receptors (PARs) have been identified, with distinct N-terminal cleavage sites and tethered ligand pharmacology. In addition to the progress in the generation of PAR-1 antagonists, we describe the role of thrombin in such processes as wound healing and the evidence implicating PAR-1 in vascular disorders and cancer. We also identify advances in the understanding of PAR-1-mediated intracellular signaling and receptor desensitization. The cellular functions, signaling events, and desensitization processes involved in PAR-2 activation are also assessed. However, other major aspects of PAR-2 are highlighted, in particular the ability of several serine protease enzymes, in addition to trypsin, to function as activators of PAR-2. The likely physiological and pathophysiological roles for PAR-2 in skin, intestine, blood vessels, and the peripheral nervous system are considered in the context of PAR-2 activation by multiple serine proteases. The recent discovery of PAR-3 and PAR-4 as additional thrombin-sensitive PARs further highlights the complexity in assessing the effects of thrombin in several different systems, an issue that remains to be fully addressed. These discoveries have also highlighted possible PAR-PAR interactions at both functional and molecular levels. The future identification of other PARs and their modes of activation are an important future direction for this expanding field of study.
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              The systemic inflammatory response syndrome and cardiopulmonary bypass.

              Cardiac surgery using cardiopulmonary bypass (CPB) provokes a systemic inflammatory response. This is mainly triggered by contact activation of blood by artificial surfaces of the extracorporeal circuit. Although often remaining sub-clinical and resolving promptly at the end of CPB, in its most extreme form this inflammatory response may be associated with the development of the systemic inflammatory response syndrome (SIRS) that can often lead to major organ dysfunction (MODs) and death. Here, we review the pathophysiology behind the development of this "whole body" inflammatory response and some of the methods currently used to minimise it.
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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
                23 May 2019
                2019
                : 13
                : 1791-1801
                Affiliations
                [1 ]Ege University, Faculty of Pharmacy, Department of Pharmacology , 35100 Bornova, Izmir, Turkey
                [2 ]Ege University, Faculty of Pharmacy, Department of Clinical Pharmacy , 35100 Bornova, Izmir, Turkey
                [3 ]Optimed Hospital, Department of Cardiovascular Surgery , 59500 Corlu, Tekirdag, Turkey
                Author notes
                Correspondence: Buket ReelEge University, Faculty of Pharmacy, Department of Clinical Pharmacy , 35100Bornova, Izmir, TurkeyTel +90 232 311 3286Fax +90 232 388 4687Email buket.reel@ 123456gmail.com
                Article
                187842
                10.2147/DDDT.S187842
                6536710
                48ef0720-0b95-4819-a332-41c0bd7c90bf
                © 2019 Saeed 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).

                History
                : 01 October 2018
                : 26 March 2019
                Page count
                Figures: 5, Tables: 1, References: 44, Pages: 11
                Categories
                Original Research

                Pharmacology & Pharmaceutical medicine
                hydrogen peroxide,doxycycline,oxidative stress,matrix metalloproteinase,human saphenous vein

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