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Article: Lipocalin-2 induces cardiomyocyte apoptosis by increasing intracellular iron accumulation
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TitleLipocalin-2 induces cardiomyocyte apoptosis by increasing intracellular iron accumulation
 
AuthorsXu, G3
Ahn, J3
Chang, S3
Eguchi, M1 3
Ogier, A3
Han, S3
Park, Y3
Shim, C4
Jang, Y4
Yang, B2
Xu, A2
Wang, Y2
Sweeney, G1 3
 
Issue Date2012
 
PublisherAmerican Society for Biochemistry and Molecular Biology, Inc. The Journal's web site is located at http://www.jbc.org/
 
CitationJournal of Biological Chemistry, 2012, v. 287 n. 7, p. 4808-4817 [How to Cite?]
DOI: http://dx.doi.org/10.1074/jbc.M111.275719
 
AbstractOur objective was to determine whether lipocalin-2 (Lcn2) regulates cardiomyocyte apoptosis, the mechanisms involved, and the functional significance. Emerging evidence suggests that Lcn2 is a proinflammatory adipokine associated with insulin resistance and obesity-related complications, such as heart failure. Here, we used both primary neonatal rat cardiomyocytes and H9c2 cells and demonstrated for the first time that Lcn2 directly induced cardiomyocyte apoptosis, an important component of cardiac remodeling leading to heart failure. This was shown by detection of DNA fragmentation using TUNEL assay, phosphatidylserine exposure using flow cytometry to detect annexin V-positive cells, caspase-3 activity using enzymatic assay and immunofluorescence, and Western blotting for the detection of cleaved caspase-3. We also observed that Lcn2 caused translocation of the proapoptotic protein Bax to mitochondria and disruption of mitochondrial membrane potential. Using transient transfection of GFP-Bax, we confirmed that Lcn2 induced co-localization of Bax with MitoTracker(R) dye. Importantly, we used the fluorescent probe Phen Green SK to demonstrate an increase in intracellular iron in response to Lcn2, and depleting intracellular iron using an iron chelator prevented Lcn2-induced cardiomyocyte apoptosis. Administration of recombinant Lcn2 to mice for 14 days increased cardiomyocyte apoptosis as well as an acute inflammatory response with compensatory changes in cardiac functional parameters. In conclusion, Lcn2-induced cardiomyocyte apoptosis is of physiological significance and occurs via a mechanism involving elevated intracellular iron levels and Bax translocation.
 
ISSN0021-9258
2013 Impact Factor: 4.600
 
DOIhttp://dx.doi.org/10.1074/jbc.M111.275719
 
PubMed Central IDPMC3281654
 
DC FieldValue
dc.contributor.authorXu, G
 
dc.contributor.authorAhn, J
 
dc.contributor.authorChang, S
 
dc.contributor.authorEguchi, M
 
dc.contributor.authorOgier, A
 
dc.contributor.authorHan, S
 
dc.contributor.authorPark, Y
 
dc.contributor.authorShim, C
 
dc.contributor.authorJang, Y
 
dc.contributor.authorYang, B
 
dc.contributor.authorXu, A
 
dc.contributor.authorWang, Y
 
dc.contributor.authorSweeney, G
 
dc.date.accessioned2012-08-16T05:54:11Z
 
dc.date.available2012-08-16T05:54:11Z
 
dc.date.issued2012
 
dc.description.abstractOur objective was to determine whether lipocalin-2 (Lcn2) regulates cardiomyocyte apoptosis, the mechanisms involved, and the functional significance. Emerging evidence suggests that Lcn2 is a proinflammatory adipokine associated with insulin resistance and obesity-related complications, such as heart failure. Here, we used both primary neonatal rat cardiomyocytes and H9c2 cells and demonstrated for the first time that Lcn2 directly induced cardiomyocyte apoptosis, an important component of cardiac remodeling leading to heart failure. This was shown by detection of DNA fragmentation using TUNEL assay, phosphatidylserine exposure using flow cytometry to detect annexin V-positive cells, caspase-3 activity using enzymatic assay and immunofluorescence, and Western blotting for the detection of cleaved caspase-3. We also observed that Lcn2 caused translocation of the proapoptotic protein Bax to mitochondria and disruption of mitochondrial membrane potential. Using transient transfection of GFP-Bax, we confirmed that Lcn2 induced co-localization of Bax with MitoTracker(R) dye. Importantly, we used the fluorescent probe Phen Green SK to demonstrate an increase in intracellular iron in response to Lcn2, and depleting intracellular iron using an iron chelator prevented Lcn2-induced cardiomyocyte apoptosis. Administration of recombinant Lcn2 to mice for 14 days increased cardiomyocyte apoptosis as well as an acute inflammatory response with compensatory changes in cardiac functional parameters. In conclusion, Lcn2-induced cardiomyocyte apoptosis is of physiological significance and occurs via a mechanism involving elevated intracellular iron levels and Bax translocation.
 
dc.description.naturelink_to_OA_fulltext
 
dc.identifier.citationJournal of Biological Chemistry, 2012, v. 287 n. 7, p. 4808-4817 [How to Cite?]
DOI: http://dx.doi.org/10.1074/jbc.M111.275719
 
dc.identifier.doihttp://dx.doi.org/10.1074/jbc.M111.275719
 
dc.identifier.epage4817
 
dc.identifier.hkuros205680
 
dc.identifier.hkuros219910
 
dc.identifier.issn0021-9258
2013 Impact Factor: 4.600
 
dc.identifier.issue7
 
dc.identifier.openurl
 
dc.identifier.pmcidPMC3281654
 
dc.identifier.pmid22117066
 
dc.identifier.scopuseid_2-s2.0-84863127635
 
dc.identifier.spage4808
 
dc.identifier.urihttp://hdl.handle.net/10722/159703
 
dc.identifier.volume287
 
dc.languageeng
 
dc.publisherAmerican Society for Biochemistry and Molecular Biology, Inc. The Journal's web site is located at http://www.jbc.org/
 
dc.publisher.placeUnited States
 
dc.relation.ispartofJournal of Biological Chemistry
 
dc.rightsJournal of Biological Chemistry. Copyright © American Society for Biochemistry and Molecular Biology, Inc.
 
dc.rightsThis research was originally published in [Journal Name]. Author(s). Title. Journal Name. Year. Vol:pp-pp. © the American Society for Biochemistry and Molecular Biology
 
dc.subject.meshAcute-Phase Proteins - metabolism - pharmacology
 
dc.subject.meshApoptosis - drug effects - physiology
 
dc.subject.meshLipocalins - metabolism - pharmacology
 
dc.subject.meshMyocytes, Cardiac - cytology - metabolism
 
dc.subject.meshOncogene Proteins - metabolism - pharmacology
 
dc.titleLipocalin-2 induces cardiomyocyte apoptosis by increasing intracellular iron accumulation
 
dc.typeArticle
 
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<contributor.author>Ogier, A</contributor.author>
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<contributor.author>Park, Y</contributor.author>
<contributor.author>Shim, C</contributor.author>
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<contributor.author>Yang, B</contributor.author>
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Author Affiliations
  1. York University
  2. The University of Hong Kong
  3. Institut Pasteur Korea
  4. Yonsei University College of Medicine