title: Obesity improves myocardial ischaemic tolerance and RISK signalling in insulin-insensitive rats.
abstract: Obesity 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 δ-opioid receptor (δ-OR) phospho-regulation of pro-survival (Akt/PKB, Erk1/2, eNOS) and pro-injury (GSK3β) enzymes were also examined. OB rats were heavier (764 ± 25 versus 657 ± 22 g for CD; P<0.05), hyperleptinaemic (11.1 ± 0.7 versus 5.0 ± 0.7 for CD; P<0.01) and comparably insulin-insensitive (HOMA-IR of 63.2 ± 3.3 versus 63.2 ± 1.6 for CD). In vivo infarction was more than halved in OB (20 ± 3%) versus CD rats (45 ± 6% P<0.05), as was post-ischaemic lactate dehydrogenase efflux (0.4 ± 0.3 mU/ml versus 5.6 ± 0.5 mU/ml; P<0.02) and ex vivo contractile dysfunction (62 ± 2% versus 44 ± 6% recovery of ventricular force; P<0.05). OB hearts exhibited up to 60% higher Akt expression, with increased phosphorylation of eNOS (+100%), GSK3β (+45%) and Erk1/2 (+15%). Pre-ischaemic δ-OR agonism with BW373U86 improved recoveries in CD hearts in association with phosphorylation of Akt (+40%), eNOS (+75%) and GSK3β (+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 δ-OR agonism.
authors.affiliation: Heart Foundation Research Centre, Griffith Health Institute, Griffith University Gold Coast, QLD 4217, Australia.
authors.forename: Daniel
authors.initials: D
authors.lastname: Donner
authors.forename: John P
authors.initials: JP
authors.lastname: Headrick
authors.forename: Jason N
authors.initials: JN
authors.lastname: Peart
authors.forename: Eugene F
authors.initials: EF
authors.lastname: du Toit
mesh_terms: D000818:Animals; D001549:Benzamides / Q000494:pharmacology; D002316:Cardiotonic Agents / Q000494:pharmacology / Q000627:therapeutic use; D004040:Dietary Carbohydrates / Q000008:administration & dosage / Q000494:pharmacology; D006801:Humans; D066298:In Vitro Techniques; D007328:Insulin / Q000494:pharmacology*; D009200:Myocardial Contraction / Q000187:drug effects; D009203:Myocardial Infarction / Q000150:complications / Q000473:pathology / Q000503:physiopathology; D017202:Myocardial Ischemia / Q000150:complications / Q000201:enzymology / Q000473:pathology* / Q000503:physiopathology; D015428:Myocardial Reperfusion Injury / Q000150:complications / Q000201:enzymology / Q000473:pathology / Q000503:physiopathology; D019001:Nitric Oxide Synthase / Q000378:metabolism; D009765:Obesity / Q000150:complications / Q000201:enzymology* / Q000473:pathology / Q000503:physiopathology; D010766:Phosphorylation / Q000187:drug effects; D010879:Piperazines / Q000494:pharmacology; D011494:Protein Kinases / Q000378:metabolism*; D051381:Rats; D017465:Receptors, Opioid, delta / Q000819:agonists / Q000378:metabolism; D015398:Signal Transduction / Q000187:drug effects*; D013851:Thinness / Q000150:complications / Q000201:enzymology / Q000473:pathology / Q000503:physiopathology
chemical_list: D001549:Benzamides; D002316:Cardiotonic Agents; D004040:Dietary Carbohydrates; D007328:Insulin; D010879:Piperazines; D017465:Receptors, Opioid, delta; C083877:BW 373U86; D019001:Nitric Oxide Synthase; D011494:Protein Kinases