Long-chain free fatty acids inhibit ischaemic preconditioning of the isolated rat heart
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Long‑chain free fatty acids inhibit ischaemic preconditioning of the isolated rat heart Amanda Lochner1 · Sonia Genade1 · Amanda Genis1 · Erna Marais1 · Ruduwaan Salie1 Received: 16 January 2020 / Accepted: 18 June 2020 © Springer Science+Business Media, LLC, part of Springer Nature 2020
Abstract 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 agematched 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. Keywords Ischaemic preconditioning · Isolated perfused rat hearts · Palmitate · Glucose · Dichloroacetate · Infarct size · Functional recovery
Introduction Although it is generally accepted that obesity, dyslipidaemia and insulin resistance reduce the tolerance to myocardial ischaemia [1–3], recent reports that obesity in humans is associated with reduced morbidity and mortality (the socalled obesity paradox) [4–6] have elicited much interest. Data obtained in experimental studies on the impact of these * Amanda Lochner [email protected] 1
Division of Medical Physiology, Department of Biomedical Sciences, Faculty of Medicine and Health Sciences, University of Stellenbo
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