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Article: PKCβ inhibition with ruboxistaurin reduces oxidative stress and attenuates left ventricular hypertrophy and dysfuntion in rats with streptozotocin-induced diabetes

TitlePKCβ inhibition with ruboxistaurin reduces oxidative stress and attenuates left ventricular hypertrophy and dysfuntion in rats with streptozotocin-induced diabetes
Authors
KeywordsDiabetic cardiomyopathy
Left ventricular hypertrophy
Oxidative stress
Protein kinase cβ
Ruboxistaurin
Issue Date2012
PublisherPortland Press Ltd. The Journal's web site is located at http://www.clinsci.org/
Citation
Clinical Science, 2012, v. 122 n. 4, p. 161-173 How to Cite?
AbstractOxidative stress plays critical roles in the development of diabetic cardiovascular complications, including myocardial hypertrophy. The β isoform of PKC (protein kinase C) is preferentially overexpressed in themyocardium of diabetic subjects accompanied with increased activation of the pro-oxidant enzyme NADPH oxidase, which may exacerbate oxidative stress. We hypothesized that myocardial PKCβ is a major upstream mediator of oxidative stress in diabetes and that PKCβ inhibition can attenuate myocardial hypertrophy and dysfunction. Control or streptozotocininduced diabetic rats were treated with the selective PKCβ inhibitor RBX (ruboxistaurin; 1 mg/kg of body weight per day) or the antioxidant NAC (N-acetylcysteine) for 4 weeks. LV (left ventricular) dimensions and functions were detected by echocardiography. 15-F 2t-isoprostane (a specific index of oxidative stress) and myocardial activities of superoxide dismutase as well as protein levels of NADPH oxidase were assessed by immunoassay or Western blotting. Echocardiography revealed that the LV mass/body weight ratio was significantly increased in diabetic rats (P<0.01 compared with the control group) in parallel with the impaired LV relaxation. A significant increase in cardiomyocyte cross-sectional area was observed in diabetic rats accompanied by an increased production of O 2 - (superoxide anion) and 15-F 2t-isoprostane (all P<0.05 compared with the control group). RBX normalized these changes with concomitant inhibition of PKCβ 2 activation and prevention of NADPH oxidase subunit p67 phox membrane translocation and p22 phox overexpression. The effects of RBX were comparable with that of NAC, except that NAC was inferior to RBX in attenuating cardiac dysfunction. It is concluded that RBX can ameliorate myocardial hypertrophy and dysfunction in diabetes, which may represent a novel therapy in the prevention of diabetic cardiovascular complications. © The Authors Journal compilation © 2012 Biochemical Society.
Persistent Identifierhttp://hdl.handle.net/10722/147286
ISSN
2015 Impact Factor: 4.996
2015 SCImago Journal Rankings: 2.427
ISI Accession Number ID
Funding AgencyGrant Number
Research Grants Council of Hong Kong (GRF)781 109 M
766 709 M
784011 M
Funding Information:

This work was supported by the Research Grants Council of Hong Kong (GRF) [grant numbers 781 109 M, 766 709 M, 784011 M].

References

 

DC FieldValueLanguage
dc.contributor.authorLiu, Yen_HK
dc.contributor.authorLei, Sen_HK
dc.contributor.authorGao, Xen_HK
dc.contributor.authorMao, Xen_HK
dc.contributor.authorWang, Ten_HK
dc.contributor.authorWong, GTen_HK
dc.contributor.authorVanhoutte, PMen_HK
dc.contributor.authorIrwin, MGen_HK
dc.contributor.authorXia, Zen_HK
dc.date.accessioned2012-05-29T06:01:15Z-
dc.date.available2012-05-29T06:01:15Z-
dc.date.issued2012en_HK
dc.identifier.citationClinical Science, 2012, v. 122 n. 4, p. 161-173en_HK
dc.identifier.issn0143-5221en_HK
dc.identifier.urihttp://hdl.handle.net/10722/147286-
dc.description.abstractOxidative stress plays critical roles in the development of diabetic cardiovascular complications, including myocardial hypertrophy. The β isoform of PKC (protein kinase C) is preferentially overexpressed in themyocardium of diabetic subjects accompanied with increased activation of the pro-oxidant enzyme NADPH oxidase, which may exacerbate oxidative stress. We hypothesized that myocardial PKCβ is a major upstream mediator of oxidative stress in diabetes and that PKCβ inhibition can attenuate myocardial hypertrophy and dysfunction. Control or streptozotocininduced diabetic rats were treated with the selective PKCβ inhibitor RBX (ruboxistaurin; 1 mg/kg of body weight per day) or the antioxidant NAC (N-acetylcysteine) for 4 weeks. LV (left ventricular) dimensions and functions were detected by echocardiography. 15-F 2t-isoprostane (a specific index of oxidative stress) and myocardial activities of superoxide dismutase as well as protein levels of NADPH oxidase were assessed by immunoassay or Western blotting. Echocardiography revealed that the LV mass/body weight ratio was significantly increased in diabetic rats (P<0.01 compared with the control group) in parallel with the impaired LV relaxation. A significant increase in cardiomyocyte cross-sectional area was observed in diabetic rats accompanied by an increased production of O 2 - (superoxide anion) and 15-F 2t-isoprostane (all P<0.05 compared with the control group). RBX normalized these changes with concomitant inhibition of PKCβ 2 activation and prevention of NADPH oxidase subunit p67 phox membrane translocation and p22 phox overexpression. The effects of RBX were comparable with that of NAC, except that NAC was inferior to RBX in attenuating cardiac dysfunction. It is concluded that RBX can ameliorate myocardial hypertrophy and dysfunction in diabetes, which may represent a novel therapy in the prevention of diabetic cardiovascular complications. © The Authors Journal compilation © 2012 Biochemical Society.en_HK
dc.languageengen_US
dc.publisherPortland Press Ltd. The Journal's web site is located at http://www.clinsci.org/en_HK
dc.relation.ispartofClinical Scienceen_HK
dc.subjectDiabetic cardiomyopathyen_HK
dc.subjectLeft ventricular hypertrophyen_HK
dc.subjectOxidative stressen_HK
dc.subjectProtein kinase cβen_HK
dc.subjectRuboxistaurinen_HK
dc.titlePKCβ inhibition with ruboxistaurin reduces oxidative stress and attenuates left ventricular hypertrophy and dysfuntion in rats with streptozotocin-induced diabetesen_HK
dc.typeArticleen_HK
dc.identifier.emailWong, GT: gordon@hku.hken_HK
dc.identifier.emailVanhoutte, PM: vanhoutt@hku.hken_HK
dc.identifier.emailIrwin, MG: mgirwin@hku.hken_HK
dc.identifier.emailXia, Z: zyxia@hkucc.hku.hken_HK
dc.identifier.authorityWong, GT=rp00523en_HK
dc.identifier.authorityVanhoutte, PM=rp00238en_HK
dc.identifier.authorityIrwin, MG=rp00390en_HK
dc.identifier.authorityXia, Z=rp00532en_HK
dc.description.naturelink_to_subscribed_fulltexten_US
dc.identifier.doi10.1042/CS20110176en_HK
dc.identifier.scopuseid_2-s2.0-84555203690en_HK
dc.identifier.hkuros203042-
dc.relation.referenceshttp://www.scopus.com/mlt/select.url?eid=2-s2.0-84555203690&selection=ref&src=s&origin=recordpageen_HK
dc.identifier.volume122en_HK
dc.identifier.issue4en_HK
dc.identifier.spage161en_HK
dc.identifier.epage173en_HK
dc.identifier.eissn1470-8736-
dc.identifier.isiWOS:000300123700007-
dc.publisher.placeUnited Kingdomen_HK
dc.identifier.scopusauthoridLiu, Y=37115892000en_HK
dc.identifier.scopusauthoridLei, S=35208515200en_HK
dc.identifier.scopusauthoridGao, X=7403872975en_HK
dc.identifier.scopusauthoridMao, X=54795570800en_HK
dc.identifier.scopusauthoridWang, T=54796342500en_HK
dc.identifier.scopusauthoridWong, GT=19637815700en_HK
dc.identifier.scopusauthoridVanhoutte, PM=7202304247en_HK
dc.identifier.scopusauthoridIrwin, MG=7202411076en_HK
dc.identifier.scopusauthoridXia, Z=7402151748en_HK

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