Erythropoietin Decreases the Occurrence of Myocardial Fibrosis by Inhibiting the NADPH-ERK-NF-κB Pathway

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Abstract

Objectives: The aim of this study was to investigate the protective role of erythropoietin (EPO) against myocardial fibrosis (MF). Methods: Pressure-overloaded rats were established by abdominal aortic constriction, the rats were randomly divided in a double-blind manner into 3 groups (n = 12 for each group): sham-operated rats (sham), operated rats receiving physiological saline (vehicle) and operated rats receiving 4,000 U/kg rhEPO (EPO group). The vehicle and drugs were administered to rats by intraperitoneal injection. In addition, cultured adult rat cardiac fibroblasts (CFs) were utilized to investigate the role of EPO in CF proliferation and collagen secretion. Results: After 4 weeks, besides an increase in blood pressure, myocardial hypertrophy, collagen deposition in the myocardium and decreased cardiac function were observed in the pressure-overloaded rats. The expression of NADPH oxidase (Nox2 and Nox4) and inflammatory cytokines (CD45, F4/80 and MCP-1) was also significantly increased. All these alterations were prevented by EPO. TGF-ß promoted CF proliferation, collagen secretion, ROS production and Nox2/Nox4 expression, which was inhibited by EPO. In addition, the TGF-ß-induced increase of ERK1/2 phosphorylation and NF-κB expression were attenuated by EPO. Conclusion: EPO inhibited rat MF induced by pressure overload and improved myocardial function by decreasing CF proliferation and differentiation via inhibition of the NADPH-ERK-NF-κB pathway.

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NADPH oxidase 4 (Nox4) is a major source of oxidative stress in the failing heart.

Junya Kuroda, Tetsuro Ago, Shouji Matsushima … (2010)

NAD(P)H oxidases (Noxs) produce O(2)(-) and play an important role in cardiovascular pathophysiology. The Nox4 isoform is expressed primarily in the mitochondria in cardiac myocytes. To elucidate the function of endogenous Nox4 in the heart, we generated cardiac-specific Nox4(-/-) (c-Nox4(-/-)) mice. Nox4 expression was inhibited in c-Nox4(-/-) mice in a heart-specific manner, and there was no compensatory up-regulation in other Nox enzymes. These mice exhibited reduced levels of O(2)(-) in the heart, indicating that Nox4 is a significant source of O(2)(-) in cardiac myocytes. The baseline cardiac phenotype was normal in young c-Nox4(-/-) mice. In response to pressure overload (PO), however, increases in Nox4 expression and O(2)(-) production in mitochondria were abolished in c-Nox4(-/-) mice, and c-Nox4(-/-) mice exhibited significantly attenuated cardiac hypertrophy, interstitial fibrosis and apoptosis, and better cardiac function compared with WT mice. Mitochondrial swelling, cytochrome c release, and decreases in both mitochondrial DNA and aconitase activity in response to PO were attenuated in c-Nox4(-/-) mice. On the other hand, overexpression of Nox4 in mouse hearts exacerbated cardiac dysfunction, fibrosis, and apoptosis in response to PO. These results suggest that Nox4 in cardiac myocytes is a major source of mitochondrial oxidative stress, thereby mediating mitochondrial and cardiac dysfunction during PO.

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Redox signaling in cardiac myocytes

Celio Santos, Narayana Anilkumar, Min Zhang … (2011)

The heart has complex mechanisms that facilitate the maintenance of an oxygen supply–demand balance necessary for its contractile function in response to physiological fluctuations in workload as well as in response to chronic stresses such as hypoxia, ischemia, and overload. Redox-sensitive signaling pathways are centrally involved in many of these homeostatic and stress-response mechanisms. Here, we review the main redox-regulated pathways that are involved in cardiac myocyte excitation–contraction coupling, differentiation, hypertrophy, and stress responses. We discuss specific sources of endogenously generated reactive oxygen species (e.g., mitochondria and NADPH oxidases of the Nox family), the particular pathways and processes that they affect, the role of modulators such as thioredoxin, and the specific molecular mechanisms that are involved—where this knowledge is available. A better understanding of this complex regulatory system may allow the development of more specific therapeutic strategies for heart diseases.

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A comparison of high-dose recombinant erythropoietin treatment regimens in brain-injured neonatal rats.

Ronald J. McPherson, B Kellert, Sandra E. Juul (2007)

Recombinant human erythropoietin (rEpo) is neuroprotective in neonatal models of hypoxic-ischemic brain injury. However, the optimal rEpo dose, dosing interval, and number of doses for reducing brain injury are still undetermined. We compared the neuroprotective efficacy of several subcutaneous rEpo treatment regimens. Seven-day-old rats underwent unilateral carotid ligation plus 90 min 8% hypoxia. Treatment began immediately after injury. Treatment regimens examined included 1, 3, or 7 daily subcutaneous injections of either 0 (vehicle), 2,500, 5,000, or 30,000 U/kg rEpo. Gross brain injury, neuronal apoptosis (TUNEL), and gliosis (glial fibrillary acidic protein) were assessed at 48 h or 1 wk post injury. Immunoreactive cells and brain injury were quantified for statistical comparison to vehicle controls. rEpo treatment reduced brain injury, apoptosis, and gliosis, in a dose-dependent U-shaped manner at both 48 h and 1 wk. Neither one injection of 2,500, seven injections of 5,000, or three injections of 30,000 U/kg rEpo were protective. Three doses of 5,000 and one dose of 30,000 U/kg rEpo were most protective at both time intervals. rEpo provides dose-dependent neuroprotection. Of the regimens tested, three doses of 5,000 U/kg was optimal because it provided maximal benefit with limited total exposure.

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Journal

Journal ID (publisher-id): CRD

Journal ID (nlm-ta): Cardiology

Journal ID (doi): 10.1159/issn.0008-6312

Title: Cardiology

Publisher: S. Karger AG

ISSN (Print): 0008-6312

ISSN (Electronic): 1421-9751

Publication date Subscription-year: 2016

Publication date (Print): January 2016

Publication date (Electronic): 30 October 2015

Volume: 133

Issue: 2

Pages: 97-108

Affiliations

Department of Physiology and Tangshan Key Laboratory for Preclinical and Basic Research on Chronic Diseases, School of Basic Medical Science, North China University of Science and Technology, Tangshan, China

Author notes

*Li-Ping Wang, School of Basic Medical Science, North China University of Science and Technology, No. 57, Jianshe South Road, Tangshan, Hebei 063000 (China), E-Mail mywlpzjm@163.com

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Li-Ping Wang https://orcid.org/0000-0002-9350-3525

Article

Publisher ID: 440995 Other ID: Cardiology 2016;133:97-108

DOI: 10.1159/000440995

PubMed ID: 26513353

SO-VID: 1ac60993-3d88-4050-ad48-de3268c06cd8

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Copyright: All rights reserved. No part of this publication may be translated into other languages, reproduced or utilized in any form or by any means, electronic or mechanical, including photocopying, recording, microcopying, or by any information storage and retrieval system, without permission in writing from the publisher. Drug Dosage: The authors and the publisher have exerted every effort to ensure that drug selection and dosage set forth in this text are in accord with current recommendations and practice at the time of publication. However, in view of ongoing research, changes in government regulations, and the constant flow of information relating to drug therapy and drug reactions, the reader is urged to check the package insert for each drug for any changes in indications and dosage and for added warnings and precautions. This is particularly important when the recommended agent is a new and/or infrequently employed drug. Disclaimer: The statements, opinions and data contained in this publication are solely those of the individual authors and contributors and not of the publishers and the editor(s). The appearance of advertisements or/and product references in the publication is not a warranty, endorsement, or approval of the products or services advertised or of their effectiveness, quality or safety. The publisher and the editor(s) disclaim responsibility for any injury to persons or property resulting from any ideas, methods, instructions or products referred to in the content or advertisements.

History

Date received : 14 April 2015

Date accepted : 05 September 2015

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Figures: 8, Tables: 2, References: 37, Pages: 12

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Erythropoietin Decreases the Occurrence of Myocardial Fibrosis by Inhibiting the NADPH-ERK-NF-κB Pathway

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Karger: Cardiovascular System

Most cited references 27

NADPH oxidase 4 (Nox4) is a major source of oxidative stress in the failing heart.

Redox signaling in cardiac myocytes

A comparison of high-dose recombinant erythropoietin treatment regimens in brain-injured neonatal rats.

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Cited by 3

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