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dc.contributor.authorDonner, Daniel
dc.contributor.authorHeadrick, John P
dc.contributor.authorPeart, Jason N
dc.contributor.authordu Toit, Eugene F
dc.date.accessioned2018-03-19T01:31:03Z
dc.date.available2018-03-19T01:31:03Z
dc.date.issued2013
dc.date.modified2013-06-21T02:54:59Z
dc.identifier.issn1754-8403
dc.identifier.doi10.1242/dmm.010959
dc.identifier.urihttp://hdl.handle.net/10072/51742
dc.description.abstractObesity with associated metabolic disturbances worsens ischaemic heart disease outcomes, and rodent studies confirm that obesity with insulin-resistance impairs myocardial resistance to ischemia-reperfusion (I-R) injury. However, the effects of obesity per se are unclear, with some evidence for paradoxic cardioprotection (particularly in older subjects). We tested the impact of dietary obesity on I-R tolerance and reperfusion injury salvage kinase (RISK) signalling in hearts from middle-aged (10 months old) insulin-insensitive rats. Hearts from Wistar rats on either a 32-week control (CD) or high carbohydrate obesogenic (OB) diet were assessed for I-R resistance in vivo (45 minutes left anterior descending artery occlusion and 120 minutes reperfusion) and ex vivo (25 minutes ischemia and 60 minutes reperfusion). Expression and d-opioid receptor (d-OR) phospho-regulation of pro-survival (Akt/PKB, Erk1/2, eNOS) and pro-injury (GSK3ߩ enzymes were also examined. OB rats were heavier (764Ჵ versus 657Ჲ g for CD; P<0.05), hyperleptinaemic (11.1ᰮ7 versus 5.0ᰮ7 for CD; P<0.01) and comparably insulin-insensitive (HOMA-IR of 63.2ᳮ3 versus 63.2ᱮ6 for CD). In vivo infarction was more than halved in OB (20᳥) versus CD rats (45ᶥ P<0.05), as was post-ischaemic lactate dehydrogenase efflux (0.4ᰮ3 mU/ml versus 5.6ᰮ5 mU/ml; P<0.02) and ex vivo contractile dysfunction (62Ქ versus 44ᶥ recovery of ventricular force; P<0.05). OB hearts exhibited up to 60% higher Akt expression, with increased phosphorylation of eNOS (+100%), GSK3ߠ(+45%) and Erk1/2 (+15%). Pre-ischaemic d-OR agonism with BW373U86 improved recoveries in CD hearts in association with phosphorylation of Akt (+40%), eNOS (+75%) and GSK3ߠ(+30%), yet failed to further enhance RISK-NOS activation or I-R outcomes in OB hearts. In summary, dietary obesity in the context of age-related insulin-insensitivity paradoxically improves myocardial I-R tolerance, in association with moderate hyperleptinaemic and enhanced RISK expression and phospho-regulation. However, OB hearts are resistant to further RISK modulation and cardioprotection via acute d-OR agonism.
dc.description.peerreviewedYes
dc.description.publicationstatusYes
dc.languageEnglish
dc.language.isoeng
dc.publisherThe Company of Biologists
dc.publisher.placeUnited Kingdom
dc.relation.ispartofstudentpublicationN
dc.relation.ispartofpagefrom457
dc.relation.ispartofpageto466
dc.relation.ispartofissue2
dc.relation.ispartofjournalDisease Models & Mechanisms
dc.relation.ispartofvolume6
dc.rights.retentionY
dc.subject.fieldofresearchCardiology (incl. Cardiovascular Diseases)
dc.subject.fieldofresearchBiological Sciences
dc.subject.fieldofresearchMedical and Health Sciences
dc.subject.fieldofresearchcode110201
dc.subject.fieldofresearchcode06
dc.subject.fieldofresearchcode11
dc.titleObesity improves myocardial ischaemic tolerance and RISK signalling in insulin-insensitive rats
dc.typeJournal article
dc.type.descriptionC1 - Articles
dc.type.codeC - Journal Articles
dcterms.licensehttp://creativecommons.org/licenses/by-nc-sa/3.0
dc.description.versionVersion of Record (VoR)
gro.facultyGriffith Health, School of Medical Science
gro.rights.copyright© 2013. Published by The Company of Biologists Ltd This is an Open Access article distributed under the terms of the Creative Commons Attribution Non-Commercial Share Alike License (http://creativecommons.org/licenses/by-nc-sa/3.0), which permits unrestricted non-commercial use, distribution and reproduction in any medium provided that the original work is properly cited and all further distributions of the work or adaptation are subject to the same Creative Commons License terms.
gro.date.issued2012
gro.hasfulltextFull Text
gro.griffith.authorHeadrick, John P.
gro.griffith.authorPeart, Jason N.
gro.griffith.authorDonner, Dan G.
gro.griffith.authorDu Toit, Eugene


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