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      Circulating NOS3 Modulates Left Ventricular Remodeling following Reperfused Myocardial Infarction

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          Abstract

          Purpose

          Nitric oxide (NO) is constitutively produced and released from the endothelium and several blood cell types by the isoform 3 of the NO synthase (NOS3). We have shown that NO protects against myocardial ischemia/reperfusion (I/R) injury and that depletion of circulating NOS3 increases within 24h of ischemia/reperfusion the size of myocardial infarction (MI) in chimeric mice devoid of circulating NOS3. In the current study we hypothesized that circulating NOS3 also affects remodeling of the left ventricle following reperfused MI.

          Methods

          To analyze the role of circulating NOS3 we transplanted bone marrow of NOS3 −/− and wild type (WT) mice into WT mice, producing chimerae expressing NOS3 only in vascular endothelium (BC−/EC+) or in both, blood cells and vascular endothelium (BC+/EC+). Both groups underwent 60 min of coronary occlusion in a closed-chest model of reperfused MI. During the 3 weeks post MI, structural and functional LV remodeling was serially assessed (24h, 4d, 1w, 2w and 3w) by echocardiography. At 72 hours post MI, gene expression of several extracellular matrix (ECM) modifying molecules was determined by quantitative RT-PCR analysis. At 3 weeks post MI, hemodynamics were obtained by pressure catheter, scar size and collagen content were quantified post mortem by Gomori’s One-step trichrome staining.

          Results

          Three weeks post MI, LV end-systolic (53.2±5.9μl;***p≤0.001;n = 5) and end-diastolic volumes (82.7±5.6μl;*p<0.05;n = 5) were significantly increased in BC−/EC+, along with decreased LV developed pressure (67.5±1.8mmHg;n = 18;***p≤0.001) and increased scar size/left ventricle (19.5±1.5%;n = 13;**p≤0.01) compared to BC+/EC+ (ESV:35.6±2.2μl; EDV:69.1±2.6μl n = 8; LVDP:83.2±3.2mmHg;n = 24;scar size/LV13.8±0.7%;n = 16). Myocardial scar of BC−/EC+ was characterized by increased total collagen content (20.2±0.8%;n = 13;***p≤0.001) compared to BC+/EC+ (15.9±0.5;n = 16), and increased collagen type I and III subtypes.

          Conclusion

          Circulating NOS3 ameliorates maladaptive left ventricular remodeling following reperfused myocardial infarction.

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          Most cited references39

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          Role of oxidative stress in cardiac hypertrophy and remodeling.

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            Red blood cells express a functional endothelial nitric oxide synthase.

            The synthesis of nitric oxide (NO) in the circulation has been attributed exclusively to the vascular endothelium. Red blood cells (RBCs) have been demonstrated to carry a nonfunctional NO synthase (NOS) and, due to their huge hemoglobin content, have been assumed to metabolize large quantities of NO. More recently, however, RBCs have been identified to reversibly bind, transport, and release NO within the cardiovascular system. We now provide evidence that RBCs from humans express an active and functional endothelial-type NOS (eNOS), which is localized in the plasma membrane and the cytoplasm of RBCs. This NOS is regulated by its substrate L-arginine, by calcium, and by phosphorylation via PI3 kinase. RBC-NOS activity regulates deformability of RBC membrane and inhibits activation of platelets. The NOS-dependent conversion of L-arginine in RBCs is comparable to that of cultured human endothelial cells. RBCs in eNOS-/- mice in contrast to wild-type mice lack NOS protein and activity, strengthening the evidence of an eNOS in RBCs. These data show an eNOS-like protein and activity in RBCs serving regulatory functions in RBCs and platelets, which may stimulate new approaches in the treatment of NO deficiency states inherent to several vascular and hematologic diseases.
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              Nitric oxide in myocardial ischemia/reperfusion injury.

              Administration of nitric oxide (NO), NO donors or drugs that enhance NO release (statins, calcium antagonists, ACE-inhibitors, dexamethasone) prior to ischemia protects the myocardium against ischemia/reperfusion injury. While this exogenous administration of NO prior to ischemia can initiate a preconditioning-like phenomenon, endogenous NO-synthase (NOS)-derived NO is not involved in triggering or mediating the early phase of ischemic preconditioning's protection, but does play a pivotal role for initiating and mediating the delayed phase of ischemic preconditioning's protection. The present review now summarizes the importance of endogenous and exogenous NO when given at the time of reperfusion for vascular and myocardial function and morphological outcome following ischemia/reperfusion. Given the inconsistency of the published data, potential confounding factors that might affect experimental results on the role of NO in myocardial ischemia/reperfusion were identified, such as (1) the lack of characterization of the involved NOS isoforms in myocardial ischemia/reperfusion injury in different animal species, (2) the lack of direct measurements of myocardial NO concentration and/or NOS activity to assure sufficient NOS inhibition, (3) the lack of consideration of nonenzymatic NO production as a potential source of NO, and (4) the absence of plasma or blood components in in vitro studies influencing NO delivery and metabolism. Future research on the importance of NO in ischemia/reperfusion injury will have to focus more precisely on the identification and standardization of potential confounding experimental factors that influence synthesis, transport, and interaction of NO with various targets in blood and tissue.
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                Author and article information

                Contributors
                Role: Academic Editor
                Journal
                PLoS One
                PLoS ONE
                plos
                plosone
                PLoS ONE
                Public Library of Science (San Francisco, CA USA )
                1932-6203
                14 April 2015
                2015
                : 10
                : 4
                : e0120961
                Affiliations
                [1 ]Medical Faculty, Division of Cardiology, Pulmonology & Vascular Medicine, Heinrich-Heine-University, Düsseldorf, Germany
                [2 ]Medical Faculty, Department of Cardiovascular Physiology, Heinrich-Heine-University, Düsseldorf, Germany
                [3 ]CARID, Cardiovascular Research Institute Düsseldorf, Düsseldorf, Germany
                [4 ]Medical Faculty, Institute of Pharmacology und Clinical Pharmacology, Heinrich Heine University, Cardiovascular Research Institute Düsseldorf (CARID), Düsseldorf, Germany
                [5 ]Institute for Pathophysiology, West German Heart and Vascular Center Essen, University of Essen Medical School, Essen, Germany
                [6 ]Department of Cardiology, Vascular Medicine and Intensive Care Medicine, Robert Koch Krankenhaus, Klinikum Region Hannover, Hannover, Germany
                Virginia Commonwealth University Medical center, UNITED STATES
                Author notes

                Competing Interests: Co-author Marc Merx is a PLOS ONE Editorial Board member. This does not alter the authors' adherence to PLOS ONE Editorial policies and criteria.

                Conceived and designed the experiments: SG MS AMS MWM MK. Performed the experiments: SG MS AMS JO. Analyzed the data: SG MS AMS. Contributed reagents/materials/analysis tools: MMC TR AG JWF GH MWM MK. Wrote the paper: SG MS AMS JO MMC TR AG JWF GH MWM MK.

                Article
                PONE-D-14-41614
                10.1371/journal.pone.0120961
                4397096
                25875863
                3a1a8215-991b-49a1-8728-a30cbd58b038
                Copyright @ 2015

                This is an open access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited

                History
                : 16 September 2014
                : 27 January 2015
                Page count
                Figures: 3, Tables: 2, Pages: 12
                Funding
                This work was supported in part by ME1821/2-3 to MWM and ME1821/3-1 [FOR809] to MWM and MK, RA969/4-2 and RA969/7-2 to TR, KE405/5-1 and the SFB1116 to MK and the Susanne-Bunnenberg-Stiftung at Düsseldorf Heart Center. The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript.
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                All relevant data are within the paper and its Supporting Information files.

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