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Conference Paper: Iron overload induces mitochondria-dependent apoptosis and calpain-dependent titin proteolysis of cardiomyocytes

TitleIron overload induces mitochondria-dependent apoptosis and calpain-dependent titin proteolysis of cardiomyocytes
Authors
KeywordsCardiovascular disease
Issue Date2012
PublisherHong Kong College of Cardiology. The Journal's web site is located at http://www.hkcchk.com/journals.php#3
Citation
The 20th Annual Scientific Congress of the Hong Kong College of Cardiology (HKCC 2012), Hong Kong, 4-6 May 2012. In Journal of the Hong Kong College of Cardiology, 2012, v. 20 suppl. 1, p. A14, abstract no. 36 How to Cite?
AbstractBACKGROUND & OBJECTIVES: Cardiomyopathy secondary to iron overload is well documented in patients with beta-thalassaemia major. Nonetheless, the underlying mechanisms of iron entry into cardiomyocytes and the subsequent detrimental effects on cardiac function remain to be defined. We hypothesized that iron overload contributes to cardiac dysfunction by inducing apoptosis via mitochondria-dependent pathway, and alters the properties of the giant myofilament protein titin. MATERIALS & METHODS: Iron-overloaded HL-1 cardiomyocytes, derived from a spontaneously contracting mouse atrial cell line, were used for in vitro studies; iron-overloaded B6D2F1 mice were used for in vivo studies. Using fluorescent probes, iron was visualized dynamically and quantitatively in living HL-1 cardiomyocytes by fluorescence microscopy and quantitative fluorimetry. Using flow cytometry, phosphatidylserine exposure, active caspase-3 expression and mitochondrial membrane potential were determined in Iron-overloaded HL-1 cardiomyocytes. Immunostaining and gel electrophoresis of titin were examined in the heart tissues of Iron-overloaded mice. Activation of the upstream calcium-dependent protease of titin, calpain, was detected by FRET substrate cleavage using quantitative fluorimetry. RESULTS: We demonstrated the uptake of labile iron from culture medium to HL-1 cardiomyocytes. With intracellular accumulation of iron, HL-1 cells showed dose-dependent lost of membrane integrity, dose-dependent increase of caspase-3 activity and dose-dependent drop in mitochondrial membrane potential. In the cardiac tissue of Iron-overloaded mice, calpain activity increased significantly and titin disarray and degradation were also observed. CONCLUSION: Our findings suggest that iron overloading, through activation of calpain, causes titin proteolysis, and induces mitochondria-mediated caspase-3 dependent apoptosis in cardiomyocytes, which results in cardiac dysfunction.
DescriptionSession: Paediatric Cardiology (I) - Free Paper
Persistent Identifierhttp://hdl.handle.net/10722/147015
ISSN
2015 SCImago Journal Rankings: 0.102

 

DC FieldValueLanguage
dc.contributor.authorChen, Men_US
dc.contributor.authorChan, GCFen_US
dc.contributor.authorCheung, YFen_US
dc.date.accessioned2012-05-23T05:53:08Z-
dc.date.available2012-05-23T05:53:08Z-
dc.date.issued2012en_US
dc.identifier.citationThe 20th Annual Scientific Congress of the Hong Kong College of Cardiology (HKCC 2012), Hong Kong, 4-6 May 2012. In Journal of the Hong Kong College of Cardiology, 2012, v. 20 suppl. 1, p. A14, abstract no. 36en_US
dc.identifier.issn1027-7811-
dc.identifier.urihttp://hdl.handle.net/10722/147015-
dc.descriptionSession: Paediatric Cardiology (I) - Free Paper-
dc.description.abstractBACKGROUND & OBJECTIVES: Cardiomyopathy secondary to iron overload is well documented in patients with beta-thalassaemia major. Nonetheless, the underlying mechanisms of iron entry into cardiomyocytes and the subsequent detrimental effects on cardiac function remain to be defined. We hypothesized that iron overload contributes to cardiac dysfunction by inducing apoptosis via mitochondria-dependent pathway, and alters the properties of the giant myofilament protein titin. MATERIALS & METHODS: Iron-overloaded HL-1 cardiomyocytes, derived from a spontaneously contracting mouse atrial cell line, were used for in vitro studies; iron-overloaded B6D2F1 mice were used for in vivo studies. Using fluorescent probes, iron was visualized dynamically and quantitatively in living HL-1 cardiomyocytes by fluorescence microscopy and quantitative fluorimetry. Using flow cytometry, phosphatidylserine exposure, active caspase-3 expression and mitochondrial membrane potential were determined in Iron-overloaded HL-1 cardiomyocytes. Immunostaining and gel electrophoresis of titin were examined in the heart tissues of Iron-overloaded mice. Activation of the upstream calcium-dependent protease of titin, calpain, was detected by FRET substrate cleavage using quantitative fluorimetry. RESULTS: We demonstrated the uptake of labile iron from culture medium to HL-1 cardiomyocytes. With intracellular accumulation of iron, HL-1 cells showed dose-dependent lost of membrane integrity, dose-dependent increase of caspase-3 activity and dose-dependent drop in mitochondrial membrane potential. In the cardiac tissue of Iron-overloaded mice, calpain activity increased significantly and titin disarray and degradation were also observed. CONCLUSION: Our findings suggest that iron overloading, through activation of calpain, causes titin proteolysis, and induces mitochondria-mediated caspase-3 dependent apoptosis in cardiomyocytes, which results in cardiac dysfunction.-
dc.languageengen_US
dc.publisherHong Kong College of Cardiology. The Journal's web site is located at http://www.hkcchk.com/journals.php#3-
dc.relation.ispartofJournal of the Hong Kong College of Cardiologyen_US
dc.subjectCardiovascular disease-
dc.titleIron overload induces mitochondria-dependent apoptosis and calpain-dependent titin proteolysis of cardiomyocytesen_US
dc.typeConference_Paperen_US
dc.identifier.emailChan, GCF: gcfchan@hku.hken_US
dc.identifier.emailCheung, YF: xfcheung@hku.hken_US
dc.identifier.authorityChan, GCF=rp00431en_US
dc.identifier.authorityCheung, YF=rp00382en_US
dc.description.naturelink_to_OA_fulltext-
dc.identifier.hkuros199695en_US
dc.identifier.volume20-
dc.identifier.issuesuppl. 1-
dc.identifier.spageA14-
dc.identifier.epageA14-
dc.publisher.placeHong Kong-

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