File Download
  Links for fulltext
     (May Require Subscription)
Supplementary

Article: Lipocalin-2 induces cardiomyocyte apoptosis by increasing intracellular iron accumulation

TitleLipocalin-2 induces cardiomyocyte apoptosis by increasing intracellular iron accumulation
Authors
Issue Date2012
PublisherAmerican Society for Biochemistry and Molecular Biology, Inc. The Journal's web site is located at http://www.jbc.org/
Citation
Journal of Biological Chemistry, 2012, v. 287 n. 7, p. 4808-4817 How to Cite?
Abstract
Our 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.
Persistent Identifierhttp://hdl.handle.net/10722/159703
ISSN
2013 Impact Factor: 4.600
PubMed Central ID
ISI Accession Number ID

 

Author Affiliations
  1. York University
  2. The University of Hong Kong
  3. Institut Pasteur Korea
  4. Yonsei University College of Medicine
DC FieldValueLanguage
dc.contributor.authorXu, Gen_US
dc.contributor.authorAhn, Jen_US
dc.contributor.authorChang, Sen_US
dc.contributor.authorEguchi, Men_US
dc.contributor.authorOgier, Aen_US
dc.contributor.authorHan, Sen_US
dc.contributor.authorPark, Yen_US
dc.contributor.authorShim, Cen_US
dc.contributor.authorJang, Yen_US
dc.contributor.authorYang, Ben_US
dc.contributor.authorXu, Aen_US
dc.contributor.authorWang, Yen_US
dc.contributor.authorSweeney, Gen_US
dc.date.accessioned2012-08-16T05:54:11Z-
dc.date.available2012-08-16T05:54:11Z-
dc.date.issued2012en_US
dc.identifier.citationJournal of Biological Chemistry, 2012, v. 287 n. 7, p. 4808-4817en_US
dc.identifier.issn0021-9258en_US
dc.identifier.urihttp://hdl.handle.net/10722/159703-
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.languageengen_US
dc.publisherAmerican Society for Biochemistry and Molecular Biology, Inc. The Journal's web site is located at http://www.jbc.org/-
dc.relation.ispartofJournal of Biological Chemistryen_US
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 accumulationen_US
dc.typeArticleen_US
dc.identifier.openurlhttp://library.hku.hk:4550/resserv?sid=HKU:IR&issn=1083-351X (Electronic)0021-9258 (Linkin&volume=287&issue=7&spage=4808&epage=17&date=2012&atitle=Lipocalin-2+induces+cardiomyocyte+apoptosis+by+increasing+intracellular+iron+accumulationen_US
dc.identifier.emailXu, A: amxu@hkucc.hku.hken_US
dc.identifier.emailWang, Y: yuwanghk@hku.hken_US
dc.identifier.emailSweeney, G: gary@ip-korea.org-
dc.identifier.authorityXu, A=rp00485en_US
dc.identifier.authorityWang, Y=rp00239en_US
dc.description.naturelink_to_OA_fulltext-
dc.identifier.doi10.1074/jbc.M111.275719-
dc.identifier.pmid22117066-
dc.identifier.pmcidPMC3281654-
dc.identifier.scopuseid_2-s2.0-84863127635-
dc.identifier.hkuros205680en_US
dc.identifier.hkuros219910-
dc.identifier.volume287en_US
dc.identifier.issue7en_US
dc.identifier.spage4808en_US
dc.identifier.epage4817en_US
dc.identifier.isiWOS:000300608500042-
dc.publisher.placeUnited States-

Export via OAI-PMH Interface in XML Formats


OR


Export to Other Non-XML Formats