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Article: Exogenous expression of HIF-1α promotes cardiac differentiation of embryonic stem cells

TitleExogenous expression of HIF-1α promotes cardiac differentiation of embryonic stem cells
Authors
KeywordsCardiomyocytes
Embryonic stem cells
Hypoxia
Hypoxia inducible factor-1α
Sarcoplasmic reticulum function
Issue Date2010
PublisherAcademic Press. The Journal's web site is located at http://www.elsevier.com/locate/yjmcc
Citation
Journal Of Molecular And Cellular Cardiology, 2010, v. 48 n. 6, p. 1129-1137 How to Cite?
AbstractHypoxia plays an important role in the proliferation, differentiation and maintenance of the cardiovascular system during development. While low oxygen tension appears to direct the cultured embryonic stem cells (ESCs) to differentiate into cardiomyocytes, the underlying molecular mechanism remains unclear. At a molecular level, hypoxia inducible factor-1 (HIF-1) plays an important role in handling the hypoxia signal. In the present study, we demonstrated that expression of exogenous HIF-1α cDNA into murine ESCs significantly promoted cardiogenesis as indicated by a higher percentage of beating embryoid body and troponin-T positive cell counts as well as increased expression of early and late cardiac markers, such as GATA-binding protein 4 and 6, NK2 transcription factor related locus 5, α-myosin heavy chain, β-myosin heavy chain and myosin light chain 2 ventricular transcripts. In addition, the transduced cells exhibited increased mRNA levels of cardiotrophin-1 and vascular endothelial growth factor, along with phosphorylation of eNOS [p-eNOS (ser1171)]. Application of NOS inhibitors, diphenyleneiodonium chloride (DPI), Nω-Nitro-l-arginine methyl ester hydrochloride (l-NAME) or Nω-Nitro-l-arginine (l-NNA) abolished the HIF-1α stimulated cardiac differentiation. With the clues of upregulated mRNA expression of calcium handling proteins, ryanodine receptor 2, sodium calcium exchanger and sarcoplasmic/endoplasmic reticulum calcium ATPase, in the transduced HIF-1α ESCs, further study indicated that the maximum upstroke and decay velocity was significantly increased in both non-caffeine and caffeine-induced calcium transient in ESCs-derived cardiomyocytes. This suggests a well developed function of the sarcoplasmic reticulum in ESC-derived cardiomyocytes. Electrophysiological study also indicated that a portion of the HIF-1α-transduced cells exhibited prominent phase-4 depolarization. These findings suggest that keen activation of the HIF-1 pathway enhances differentiation and maturation of cardiomyocytes derived from ESCs. © 2010 Elsevier Ltd.
Persistent Identifierhttp://hdl.handle.net/10722/134672
ISSN
2015 Impact Factor: 4.874
2015 SCImago Journal Rankings: 2.522
ISI Accession Number ID
Funding AgencyGrant Number
National Natural Science Foundation of China (NSFC)/Research Grants Council (RGC)722/05
RGC7769/08M
HKU200707176046
Funding Information:

This work was supported by grants from the National Natural Science Foundation of China (NSFC)/Research Grants Council (RGC) Grant (722/05 to H.F.T.; M.L.F.; and R.A.L.), RGC Grant (7769/08M to H.F.T.; C.W.S.; and R.A.L.), and the HKU Small Project Funding (200707176046 to K.M.N., R.A.L., M.L.F. and H.F.T.).

References

 

DC FieldValueLanguage
dc.contributor.authorNg, KMen_HK
dc.contributor.authorLee, YKen_HK
dc.contributor.authorChan, YCen_HK
dc.contributor.authorLai, WHen_HK
dc.contributor.authorFung, MLen_HK
dc.contributor.authorLi, RAen_HK
dc.contributor.authorSiu, CWen_HK
dc.contributor.authorTse, HFen_HK
dc.date.accessioned2011-07-05T08:24:01Z-
dc.date.available2011-07-05T08:24:01Z-
dc.date.issued2010en_HK
dc.identifier.citationJournal Of Molecular And Cellular Cardiology, 2010, v. 48 n. 6, p. 1129-1137en_HK
dc.identifier.issn0022-2828en_HK
dc.identifier.urihttp://hdl.handle.net/10722/134672-
dc.description.abstractHypoxia plays an important role in the proliferation, differentiation and maintenance of the cardiovascular system during development. While low oxygen tension appears to direct the cultured embryonic stem cells (ESCs) to differentiate into cardiomyocytes, the underlying molecular mechanism remains unclear. At a molecular level, hypoxia inducible factor-1 (HIF-1) plays an important role in handling the hypoxia signal. In the present study, we demonstrated that expression of exogenous HIF-1α cDNA into murine ESCs significantly promoted cardiogenesis as indicated by a higher percentage of beating embryoid body and troponin-T positive cell counts as well as increased expression of early and late cardiac markers, such as GATA-binding protein 4 and 6, NK2 transcription factor related locus 5, α-myosin heavy chain, β-myosin heavy chain and myosin light chain 2 ventricular transcripts. In addition, the transduced cells exhibited increased mRNA levels of cardiotrophin-1 and vascular endothelial growth factor, along with phosphorylation of eNOS [p-eNOS (ser1171)]. Application of NOS inhibitors, diphenyleneiodonium chloride (DPI), Nω-Nitro-l-arginine methyl ester hydrochloride (l-NAME) or Nω-Nitro-l-arginine (l-NNA) abolished the HIF-1α stimulated cardiac differentiation. With the clues of upregulated mRNA expression of calcium handling proteins, ryanodine receptor 2, sodium calcium exchanger and sarcoplasmic/endoplasmic reticulum calcium ATPase, in the transduced HIF-1α ESCs, further study indicated that the maximum upstroke and decay velocity was significantly increased in both non-caffeine and caffeine-induced calcium transient in ESCs-derived cardiomyocytes. This suggests a well developed function of the sarcoplasmic reticulum in ESC-derived cardiomyocytes. Electrophysiological study also indicated that a portion of the HIF-1α-transduced cells exhibited prominent phase-4 depolarization. These findings suggest that keen activation of the HIF-1 pathway enhances differentiation and maturation of cardiomyocytes derived from ESCs. © 2010 Elsevier Ltd.en_HK
dc.languageengen_US
dc.publisherAcademic Press. The Journal's web site is located at http://www.elsevier.com/locate/yjmccen_HK
dc.relation.ispartofJournal of Molecular and Cellular Cardiologyen_HK
dc.subjectCardiomyocytesen_HK
dc.subjectEmbryonic stem cellsen_HK
dc.subjectHypoxiaen_HK
dc.subjectHypoxia inducible factor-1αen_HK
dc.subjectSarcoplasmic reticulum functionen_HK
dc.subject.meshAnimalsen_HK
dc.subject.meshAnoxia - metabolismen_HK
dc.subject.meshCell Differentiationen_HK
dc.subject.meshCytokines - biosynthesisen_HK
dc.subject.meshEmbryonic Stem Cells - cytologyen_HK
dc.subject.meshHeart - physiologyen_HK
dc.subject.meshHypoxia-Inducible Factor 1, alpha Subunit - biosynthesisen_HK
dc.subject.meshMiceen_HK
dc.subject.meshModels, Biologicalen_HK
dc.subject.meshMyocardium - metabolismen_HK
dc.subject.meshRNA, Messenger - metabolismen_HK
dc.subject.meshSignal Transductionen_HK
dc.subject.meshTroponin T - biosynthesisen_HK
dc.subject.meshUp-Regulationen_HK
dc.subject.meshVascular Endothelial Growth Factor A - metabolismen_HK
dc.titleExogenous expression of HIF-1α promotes cardiac differentiation of embryonic stem cellsen_HK
dc.typeArticleen_HK
dc.identifier.emailNg, KM: skykmng@hkucc.hku.hken_HK
dc.identifier.emailChan, YC: ycchan09@hku.hken_HK
dc.identifier.emailFung, ML: fungml@hkucc.hku.hken_HK
dc.identifier.emailLi, RA: ronaldli@hkucc.hku.hken_HK
dc.identifier.emailSiu, CW: cwdsiu@hkucc.hku.hken_HK
dc.identifier.emailTse, HF: hftse@hkucc.hku.hken_HK
dc.identifier.authorityNg, KM=rp01670en_HK
dc.identifier.authorityChan, YC=rp01502en_HK
dc.identifier.authorityFung, ML=rp00433en_HK
dc.identifier.authorityLi, RA=rp01352en_HK
dc.identifier.authoritySiu, CW=rp00534en_HK
dc.identifier.authorityTse, HF=rp00428en_HK
dc.description.naturelink_to_subscribed_fulltexten_US
dc.identifier.doi10.1016/j.yjmcc.2010.01.015en_HK
dc.identifier.pmid20116384-
dc.identifier.scopuseid_2-s2.0-77952670050en_HK
dc.identifier.hkuros203434-
dc.identifier.hkuros169022-
dc.identifier.hkuros179004-
dc.relation.referenceshttp://www.scopus.com/mlt/select.url?eid=2-s2.0-77952670050&selection=ref&src=s&origin=recordpageen_HK
dc.identifier.volume48en_HK
dc.identifier.issue6en_HK
dc.identifier.spage1129en_HK
dc.identifier.epage1137en_HK
dc.identifier.eissn1095-8584-
dc.identifier.isiWOS:000277944700016-
dc.publisher.placeUnited Kingdomen_HK
dc.identifier.scopusauthoridNg, KM=25122990200en_HK
dc.identifier.scopusauthoridLee, YK=25958641200en_HK
dc.identifier.scopusauthoridChan, YC=7403676116en_HK
dc.identifier.scopusauthoridLai, WH=18434390500en_HK
dc.identifier.scopusauthoridFung, ML=7101955092en_HK
dc.identifier.scopusauthoridLi, RA=7404724466en_HK
dc.identifier.scopusauthoridSiu, CW=7006550690en_HK
dc.identifier.scopusauthoridTse, HF=7006070805en_HK
dc.identifier.citeulike6641691-

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