Obesity improves myocardial ischaemic tolerance and RISK signalling in insulin-insensitive rats

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 delta-opioid receptor (delta-OR) phospho-regulation of pro-survival (Akt/PKB, Erk1/2, eNOS) and pro-injury (GSK3 beta) 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%), GSK3 beta (+45%) and Erk1/2 (+15%). Pre-ischaemic delta-OR agonism with BW373U86 improved recoveries in CD hearts in association with phosphorylation of Akt (+40%), eNOS (+75%) and GSK3 beta (+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 insulinin-sensitivity 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 delta-OR agonism.