E. F. du Toit: School of Medical Science, Griffith University, Southport, QLD 4222, Australia.
Exp Physiol. 2013 Nov;98(11):1552-64. doi: 10.1113/expphysiol.2013.074948. Epub 2013 Jul 12.
Obesity and its comorbidities (dyslipidaemia, insulin resistance and hypertension) that together constitute the metabolic syndrome are all risk factors for ischaemic heart disease. Although obesity has been reported to be an independent risk factor for congestive heart failure, whether obesity-induced heart failure develops in the absence of increased afterload (induced by hypertension) is not clear. We have previously shown that obesity with insulin resistance decreases myocardial tolerance to ischaemia-reperfusion, but the mechanism for this decreased tolerance remains unclear. We hypothesize that obesity with insulin resistance induces adverse cardiac remodelling and pump dysfunction, as well as adverse changes in myocardial prosurvival reperfusion injury salvage kinase (RISK) pathway signalling to reduce myocardial tolerance to ischaemia-reperfusion. Wistar rats were fed an obesogenic (obese group) or a standard rat chow diet (control group) for 32 weeks. Echocardiography was performed over the 32 weeks before isolated Langendorff-perfused hearts were subjected to 40 min coronary artery ligation followed by reperfusion, and functional recovery (rate-pressure product), infarct size and RISK pathway function were assessed (Western blot analysis). Obesity with insulin resistance increased myocardial lipid accumulation but had no effect on in vivo or ex vivo left ventricular structure/function. Hearts from obese rats had lower reperfusion rate-pressure products (13115 ± 562 beats min(-1) mmHg for obese rats versus 17781 ± 1109 beats min(-1) mmHg for control rats, P < 0.05) and larger infarcts (36.3 ± 5.6% of area at risk in obese rats versus 14.1 ± 2.8% of area at risk in control rats, P < 0.01) compared with control hearts. These changes were associated with reductions in RISK pathway function, with 30-50 and 40-60% reductions in Akt and glycogen synthase kinase 3 beta (GSK-3β) expression and phosphorylation, respectively, in obese rat hearts compared with control hearts. Total endothelial nitric oxide synthase expression was reduced by 25% in obese rats. We conclude that obesity with insulin resistance had no effect on basal cardiac structure or function but decreased myocardial tolerance to ischaemia-reperfusion. This reduction in ischaemic tolerance was likely to be due to compromised RISK pathway function in obese, insulin-resistant animals.
肥胖及其合并症（血脂异常、胰岛素抵抗和高血压）共同构成代谢综合征，都是缺血性心脏病的危险因素。尽管肥胖已被报道为充血性心力衰竭的独立危险因素，但在没有后负荷增加（由高血压引起）的情况下是否会发生肥胖诱导的心力衰竭尚不清楚。我们之前已经表明，肥胖伴胰岛素抵抗会降低心肌对缺血再灌注的耐受性，但这种耐受性降低的机制尚不清楚。我们假设肥胖伴胰岛素抵抗会导致心脏不良重构和泵功能障碍，以及心肌存活再灌注损伤挽救激酶（RISK）通路信号的不良变化，从而降低心肌对缺血再灌注的耐受性。Wistar 大鼠喂食致肥胖饲料（肥胖组）或标准大鼠饲料（对照组）32 周。在进行 40 分钟冠状动脉结扎后再灌注之前，对 32 周的超声心动图进行了检查，并评估了功能恢复（压力-速率乘积）、梗死面积和 RISK 通路功能（Western blot 分析）。肥胖伴胰岛素抵抗增加了心肌脂质堆积，但对体内或体外左心室结构/功能没有影响。肥胖大鼠的心脏再灌注压力-速率乘积较低（肥胖大鼠为 13115±562 次/分钟/mmHg，对照组为 17781±1109 次/分钟/mmHg，P<0.05），梗死面积较大（肥胖大鼠为危险区的 36.3±5.6%，对照组为 14.1±2.8%，P<0.01）与对照组心脏相比。这些变化与 RISK 通路功能降低有关，与对照组心脏相比，肥胖大鼠心脏中的 Akt 和糖原合酶激酶 3β（GSK-3β）表达和磷酸化分别降低了 30-50%和 40-60%。肥胖大鼠的总内皮型一氧化氮合酶表达减少了 25%。我们的结论是，肥胖伴胰岛素抵抗对基础心脏结构或功能没有影响，但降低了心肌对缺血再灌注的耐受性。这种缺血耐受性的降低可能是由于肥胖、胰岛素抵抗动物的 RISK 通路功能受损所致。
