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Article: Cardiomyopathy associated with microcirculation dysfunction in laminin α4 chain-deficient mice

TitleCardiomyopathy associated with microcirculation dysfunction in laminin α4 chain-deficient mice
Authors
Issue Date2006
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, 2006, v. 281 n. 1, p. 213-220 How to Cite?
AbstractLaminin α4 chain is a component of extracellular matrix (ECM) laminin-8 and -9 and serves dual roles as a structure protein and as a signaling molecule. The abundance of laminin α4 chain transcripts in the heart suggests an important role of this protein in cardiovascular development and function. In this study, we demonstrate that laminin α4 deficient mice gradually develop cardiac hypertrophy with impaired function. We show that depletion of laminin α4 chain did not alter the levels of dystrophin-glycoprotein complex (DGC) components or affect cell membrane integrity. No alteration in integrin β1D protein was observed in terms of expression level or distribution pattern, indicating that the postnatal development of cardiac hypertrophy and cardiomyopathy in these mice is unlikely associated with the stability of sarcolemmal DGC and integrin complexes. Moreover, cardiomyocytes isolated from Lama4-/- mutant hearts maintained their contractility in vitro. In contrast, elevated levels of hypoxia-inducible factor 1α(Hif1α) and vascular endothelial growth factor A (Vegfa) transcripts, along with multiple foci of cardiomyocyte degeneration and fibrosis suggested sustained cardiac ischemia. Electron microscopy confirmed malformed blood vessels and wide pericapillaryECMspaces, suggesting the presence of microcirculation abnormalities in Lama4-/-mutant hearts. We thus conclude that mutation in the laminin α4 chain leads to abnormal cardiovascular ECM structure that cause insufficient oxygen supply to the heart and the subsequent ischemic cardiac phenotype observed. Our study links the genetic deficiency of an ECM protein to cardiomyopathy and implies a novel pathway of idiopathic cardiomyopathy in human. © 2006 by The American Society for Biochemistry and Molecular Biology, Inc.
Persistent Identifierhttp://hdl.handle.net/10722/147534
ISSN
2015 Impact Factor: 4.258
2015 SCImago Journal Rankings: 3.151
ISI Accession Number ID
References

 

DC FieldValueLanguage
dc.contributor.authorWang, Jen_US
dc.contributor.authorHoshijima, Men_US
dc.contributor.authorLam, Jen_US
dc.contributor.authorZhou, Zen_US
dc.contributor.authorJokiel, Aen_US
dc.contributor.authorDalton, NDen_US
dc.contributor.authorHultenby, Ken_US
dc.contributor.authorRuizLozano, Pen_US
dc.contributor.authorRoss Jr, Jen_US
dc.contributor.authorTryggvason, Ken_US
dc.contributor.authorChien, KRen_US
dc.date.accessioned2012-05-29T06:04:25Z-
dc.date.available2012-05-29T06:04:25Z-
dc.date.issued2006en_US
dc.identifier.citationJournal of Biological Chemistry, 2006, v. 281 n. 1, p. 213-220en_US
dc.identifier.issn0021-9258en_US
dc.identifier.urihttp://hdl.handle.net/10722/147534-
dc.description.abstractLaminin α4 chain is a component of extracellular matrix (ECM) laminin-8 and -9 and serves dual roles as a structure protein and as a signaling molecule. The abundance of laminin α4 chain transcripts in the heart suggests an important role of this protein in cardiovascular development and function. In this study, we demonstrate that laminin α4 deficient mice gradually develop cardiac hypertrophy with impaired function. We show that depletion of laminin α4 chain did not alter the levels of dystrophin-glycoprotein complex (DGC) components or affect cell membrane integrity. No alteration in integrin β1D protein was observed in terms of expression level or distribution pattern, indicating that the postnatal development of cardiac hypertrophy and cardiomyopathy in these mice is unlikely associated with the stability of sarcolemmal DGC and integrin complexes. Moreover, cardiomyocytes isolated from Lama4-/- mutant hearts maintained their contractility in vitro. In contrast, elevated levels of hypoxia-inducible factor 1α(Hif1α) and vascular endothelial growth factor A (Vegfa) transcripts, along with multiple foci of cardiomyocyte degeneration and fibrosis suggested sustained cardiac ischemia. Electron microscopy confirmed malformed blood vessels and wide pericapillaryECMspaces, suggesting the presence of microcirculation abnormalities in Lama4-/-mutant hearts. We thus conclude that mutation in the laminin α4 chain leads to abnormal cardiovascular ECM structure that cause insufficient oxygen supply to the heart and the subsequent ischemic cardiac phenotype observed. Our study links the genetic deficiency of an ECM protein to cardiomyopathy and implies a novel pathway of idiopathic cardiomyopathy in human. © 2006 by The American Society for Biochemistry and Molecular Biology, Inc.en_US
dc.languageengen_US
dc.publisherAmerican Society for Biochemistry and Molecular Biology, Inc. The Journal's web site is located at http://www.jbc.org/en_US
dc.relation.ispartofJournal of Biological Chemistryen_US
dc.titleCardiomyopathy associated with microcirculation dysfunction in laminin α4 chain-deficient miceen_US
dc.typeArticleen_US
dc.identifier.emailZhou, Z:zhongjun@hkucc.hku.hken_US
dc.identifier.authorityZhou, Z=rp00503en_US
dc.description.naturelink_to_OA_fulltexten_US
dc.identifier.doi10.1074/jbc.M505061200en_US
dc.identifier.scopuseid_2-s2.0-33644869471en_US
dc.identifier.hkuros114795-
dc.relation.referenceshttp://www.scopus.com/mlt/select.url?eid=2-s2.0-33644869471&selection=ref&src=s&origin=recordpageen_US
dc.identifier.volume281en_US
dc.identifier.issue1en_US
dc.identifier.spage213en_US
dc.identifier.epage220en_US
dc.identifier.isiWOS:000234307200029-
dc.publisher.placeUnited Statesen_US
dc.identifier.scopusauthoridWang, J=8631854400en_US
dc.identifier.scopusauthoridHoshijima, M=7004618176en_US
dc.identifier.scopusauthoridLam, J=7201973317en_US
dc.identifier.scopusauthoridZhou, Z=8631856300en_US
dc.identifier.scopusauthoridJokiel, A=12776328600en_US
dc.identifier.scopusauthoridDalton, ND=7004627356en_US
dc.identifier.scopusauthoridHultenby, K=7005799638en_US
dc.identifier.scopusauthoridRuizLozano, P=6603836844en_US
dc.identifier.scopusauthoridRoss Jr, J=7404966841en_US
dc.identifier.scopusauthoridTryggvason, K=7102025185en_US
dc.identifier.scopusauthoridChien, KR=35902336700en_US

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