We recently reported that non-preconditioned hearts from diet-induced obese rats showed, compared to controls, a significant reduction in infarct size after ischaemia/reperfusion, whilst ischaemic preconditioning was without effect. In view of the high circulating FFA concentration in diet rats, the aims of the present study were to: (i) compare the effect of palmitate on the preconditioning potential of hearts from age-matched controls and diet rats (ii) elucidate the effects of substrate manipulation on ischaemic preconditioning. Substrate manipulation was done with dichloroacetate (DCA), which enhances glucose oxidation and decreases fatty acid oxidation. Isolated hearts from diet rats, age-matched controls or young rats, were perfused in the working mode using the following substrates: glucose (10 mM); palmitate (1.2 mM)/3% albumin) + glucose (10 mM) (HiFA + G); palmitate (1.2 mM/3% albumin) (HiFA); palmitate (0.4 mM/3% albumin) + glucose(10 mM) (LoFA + G); palmitate (0.4 mM/3% albumin) (LoFA). Hearts were preconditioned with 3 × 5 min ischaemia/reperfusion, followed by 35 min coronary ligation and 60 min reperfusion for infarct size determination (tetrazolium method) or 20 min global ischaemia/10 or 30 min reperfusion for Western blotting (ERKp44/42, PKB/Akt). Preconditioning of glucose-perfused hearts from age-matched control (but not diet) rats reduced infarct size, activated ERKp44/42 and PKB/Akt and improved functional recovery during reperfusion (ii) perfusion with HiFA + G abolished preconditioning and activation of ERKp44/42 (iii) DCA pretreatment largely reversed the harmful effects of HiFA. Hearts from non-preconditioned diet rats exhibited smaller infarcts, but could not be preconditioned, regardless of the substrate. Similar results were obtained upon substrate manipulation of hearts from young rats. Abolishment of preconditioning in diet rats may be due to altered myocardial metabolic patterns resulting from changes in circulating FA. The harmful effects of HiFA were attenuated by stimulation of glycolysis and inhibition of FA oxidation.

我们最近报道，与对照组相比，饮食诱导的肥胖大鼠的非预处理心脏显示缺血/再灌注后梗塞面积显着减少，而缺血预处理则没有效果。鉴于饮食大鼠中较高的循环FFA浓度，本研究的目的是：（i）比较棕榈酸对年龄匹配对照组和饮食大鼠心脏预处理潜能的影响（ii）阐明缺血预处理中的底物处理。用二氯乙酸盐（DCA）进行底物处理，可增强葡萄糖氧化并减少脂肪酸氧化。使用以下底物在工作模式下灌注饮食大鼠，年龄匹配的对照组或年轻大鼠的离体心脏：葡萄糖（10 mM）; 棕榈酸酯（1。2 mM）/ 3％白蛋白）+葡萄糖（10 mM）（HiFA + G）；棕榈酸酯（1.2 mM / 3％白蛋白）（HiFA）; 棕榈酸酯（0.4 mM / 3％白蛋白）+葡萄糖（10 mM）（LoFA + G）; 棕榈酸酯（0.4 mM / 3％白蛋白）（LoFA）。对心脏进行3×5分钟的缺血/再灌注预处理，然后进行35分钟的冠状动脉结扎和60分钟的再灌注以测定梗死面积（四唑法）或20分钟的整体缺血10或30分钟的再灌注以进行Western印迹（ERKp44 / 42，PKB） / Akt）。年龄相匹配的对照大鼠（而非饮食）对葡萄糖灌注心脏的预处理减少了梗塞面积，激活了ERKp44 / 42和PKB / Akt，并在再灌注期间改善了功能恢复（ii）用HiFA + G灌注消除了预处理和ERKp44 / 42（iii）DCA预处理在很大程度上逆转了HiFA的有害作用。未经预处理的饮食大鼠的心脏表现出较小的梗塞，但无论基质如何，都无法进行预处理。幼鼠心脏的底物处理获得相似的结果。饮食大鼠中取消预处理可能是由于循环FA的变化导致了心肌代谢模式的改变。HiFA的有害作用通过刺激糖酵解和抑制FA氧化而减弱。