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      Antioxidant Therapeutic Strategies for Cardiovascular Conditions Associated with Oxidative Stress

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          Abstract

          Oxidative stress (OS) refers to the imbalance between the generation of reactive oxygen species (ROS) and the ability to scavenge these ROS by endogenous antioxidant systems, where ROS overwhelms the antioxidant capacity. Excessive presence of ROS results in irreversible damage to cell membranes, DNA, and other cellular structures by oxidizing lipids, proteins, and nucleic acids. Oxidative stress plays a crucial role in the pathogenesis of cardiovascular diseases related to hypoxia, cardiotoxicity and ischemia–reperfusion. Here, we describe the participation of OS in the pathophysiology of cardiovascular conditions such as myocardial infarction, anthracycline cardiotoxicity and congenital heart disease. This review focuses on the different clinical events where redox factors and OS are related to cardiovascular pathophysiology, giving to support for novel pharmacological therapies such as omega 3 fatty acids, non-selective betablockers and microRNAs.

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          Most cited references139

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          miR-126 regulates angiogenic signaling and vascular integrity.

          Precise regulation of the formation, maintenance, and remodeling of the vasculature is required for normal development, tissue response to injury, and tumor progression. How specific microRNAs intersect with and modulate angiogenic signaling cascades is unknown. Here, we identified microRNAs that were enriched in endothelial cells derived from mouse embryonic stem (ES) cells and in developing mouse embryos. We found that miR-126 regulated the response of endothelial cells to VEGF. Additionally, knockdown of miR-126 in zebrafish resulted in loss of vascular integrity and hemorrhage during embryonic development. miR-126 functioned in part by directly repressing negative regulators of the VEGF pathway, including the Sprouty-related protein SPRED1 and phosphoinositol-3 kinase regulatory subunit 2 (PIK3R2/p85-beta). Increased expression of Spred1 or inhibition of VEGF signaling in zebrafish resulted in defects similar to miR-126 knockdown. These findings illustrate that a single miRNA can regulate vascular integrity and angiogenesis, providing a new target for modulating vascular formation and function.
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            Dysregulation of cardiogenesis, cardiac conduction, and cell cycle in mice lacking miRNA-1-2.

            MicroRNAs (miRNAs) are genomically encoded small RNAs used by organisms to regulate the expression of proteins generated from messenger RNA transcripts. The in vivo requirement of specific miRNAs in mammals through targeted deletion remains unknown, and reliable prediction of mRNA targets is still problematic. Here, we show that miRNA biogenesis in the mouse heart is essential for cardiogenesis. Furthermore, targeted deletion of the muscle-specific miRNA, miR-1-2, revealed numerous functions in the heart, including regulation of cardiac morphogenesis, electrical conduction, and cell-cycle control. Analyses of miR-1 complementary sequences in mRNAs upregulated upon miR-1-2 deletion revealed an enrichment of miR-1 "seed matches" and a strong tendency for potential miR-1 binding sites to be located in physically accessible regions. These findings indicate that subtle alteration of miRNA dosage can have profound consequences in mammals and demonstrate the utility of mammalian loss-of-function models in revealing physiologic miRNA targets.
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              MicroRNA-210 modulates endothelial cell response to hypoxia and inhibits the receptor tyrosine kinase ligand Ephrin-A3.

              MicroRNAs (miRNAs) are small non-protein-coding RNAs that function as negative gene expression regulators. In the present study, we investigated miRNAs role in endothelial cell response to hypoxia. We found that the expression of miR-210 progressively increased upon exposure to hypoxia. miR-210 overexpression in normoxic endothelial cells stimulated the formation of capillary-like structures on Matrigel and vascular endothelial growth factor-driven cell migration. Conversely, miR-210 blockade via anti-miRNA transfection inhibited the formation of capillary-like structures stimulated by hypoxia and decreased cell migration in response to vascular endothelial growth factor. miR-210 overexpression did not affect endothelial cell growth in both normoxia and hypoxia. However, anti-miR-210 transfection inhibited cell growth and induced apoptosis, in both normoxia and hypoxia. We determined that one relevant target of miR-210 in hypoxia was Ephrin-A3 since miR-210 was necessary and sufficient to down-modulate its expression. Moreover, luciferase reporter assays showed that Ephrin-A3 was a direct target of miR-210. Ephrin-A3 modulation by miR-210 had significant functional consequences; indeed, the expression of an Ephrin-A3 allele that is not targeted by miR-210 prevented miR-210-mediated stimulation of both tubulogenesis and chemotaxis. We conclude that miR-210 up-regulation is a crucial element of endothelial cell response to hypoxia, affecting cell survival, migration, and differentiation.
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                Author and article information

                Journal
                Nutrients
                Nutrients
                nutrients
                Nutrients
                MDPI
                2072-6643
                01 September 2017
                September 2017
                : 9
                : 9
                : 966
                Affiliations
                [1 ]Departamento de Ingeniería Química, Facultad de Ingeniería y Ciencias, Universidad de La Frontera, Temuco 4780000, Chile; jorge.farias@ 123456ufrontera.cl (J.G.F.); andrea.zepeda.p@ 123456gmail.com (A.B.Z.); efigueroavillalobos@ 123456gmail.com (E.F.); pablolete@ 123456gmail.com (P.L.)
                [2 ]Unidad de Cuidados Intensivos, Hospital de Niños Roberto del Río, Santiago 7500922, Chile; victor.molina.cancino@ 123456gmail.com
                [3 ]Unidad de Cuidados Intensivos Pediátricos, Hospital Clínico Pontificia Universidad Católica de Chile, Santiago 7500922, Chile
                [4 ]Laboratorio de Investigación Biomédica, Departamento de Medicina Interna, Hospital del Salvador, Santiago 7500922, Chile; r_carrasco_l@ 123456yahoo.com
                [5 ]Departamento de Cardiología, Clínica Alemana, Santiago 7500922, Chile
                [6 ]Núcleo de Investigación en Producción Alimentaria, BIOACUI, Escuela de Acuicultura, Universidad Católica de Temuco, Temuco 4780000, Chile
                [7 ]School of Health Sciences, Universidad Católica de Temuco, Temuco 4780000, Chile
                [8 ]Programa de Fisiopatología Oriente, Instituto de Ciencias Biomédicas, Facultad de Medicina, Universidad de Chile, Santiago 7500922, Chile
                Author notes
                Author information
                https://orcid.org/0000-0001-7660-9603
                https://orcid.org/0000-0002-2489-8789
                Article
                nutrients-09-00966
                10.3390/nu9090966
                5622726
                28862654
                3043708e-79d8-49a2-84c1-bf4692c20dca
                © 2017 by the authors.

                Licensee MDPI, Basel, Switzerland. This article is an open access article distributed under the terms and conditions of the Creative Commons Attribution (CC BY) license ( http://creativecommons.org/licenses/by/4.0/).

                History
                : 04 July 2017
                : 18 August 2017
                Categories
                Review

                Nutrition & Dietetics
                hypoxia,oxidative stress,cardiac tissue,microrna,omega 3 fatty acids,carvedilol,congenital heart disease

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