Distinct metabolic transcriptional patterns and Warburg effect in porcine model of ischaemic cardiomyopathy

Abstract

Abstract Background Despite improvements in therapy for heart failure, the prognosis remains poor. Energetic imbalances related to mitochondrial dysfunction, impaired oxidative phosphorylation and oxidative damage have been implicated in the pathogenesis or worsening of heart failure. Improved understanding of the metabolic alterations of the heart may provide new biomarkers or therapeutic targets. Purpose It has been speculated that aerobic glycolysis, known as the Warburg effect, may be advantageous for cell survival whereby there is the opportunity for simultaneous energy production and production of intermediary metabolites crucial for anabolic pathways that sustain cell division and maintenance, and protein synthesis (1,2). In this study, we studied a preclinical model of ischaemic cardiomyopathy to investigate transcriptional patterns in two defined areas; peri-infarct and remote locations. Specifically, we investigated if aerobic glycolysis may be present in this setting. Methods 18 female Yorkshire pigs were studied. 10 animals underwent balloon catheter myocardial infarction followed by termination at 4 weeks. A group of 8 healthy animals served as controls. All animals underwent cardiac MRI prior to termination confirming ventricular impairment and remodelling in the chronic animals (see Table 1). Gene expression profiles of glucose mobilisation and glucose metabolic markers (GLUT1, GLUT4, ANK2, GAPDH and LDHA), oxidative phosphorylation and mitochondrial function (ND1, TFAM, and PGC1-alpha), key markers of insulin resistance (AKT1, AS160) and a hypoxia marker (HIF1-alpha) were measured. Results Our results indicate the presence of two distinct metabolic profiles at the gene expression level, differing from control tissue but more interestingly with striking differences regionally. In the remote region compared to controls, we demonstrate a picture suggestive of increased glycolysis with significant transcriptional upregulation of GLUT1 and GLUT4 glucose transporters (p=0.01 and p=0.02 respectively), alongside a significant reduction in PGC1-alpha (p=0.04) with maintained transcriptional levels of LDHA and HIF1-alpha. Combined, these results are suggestive of reduced oxidative phosphorylation alongside compensated, or early stage, aerobic glycolytic metabolism in this region. In contrast, in peri-infarct tissue versus controls, we demonstrate a reduction in glycolysis (GLUT1 p=0.09, GLUT4 p=0.01 with a dramatic increase in GLUT1/GLUT4 ratio of 6.7 times) and reduced markers of mitochondrial function indicative of insulin-resistance with evidence of a fetal-pattern metabolic profile (see Table 2 for detailed results). Conclusions This study demonstrates distinct transcriptional profiles within hearts with ischaemic cardiomyopathy and for the first time suggests that the Warburg effect may be present in remote myocardium in this setting supporting the need for further work in this area. Funding Acknowledgement Type of funding sources: Other. Main funding source(s): This research work was supported by grants awarded to Professor Ascione: the British Heart Foundation (BHF) (BHF IG/14/2/30991, BHF RM/13/2/30158), and the Medical Research Council (MRC) (MRC MR/L012723/1). Table 1. CMR parameters for animals studiedTable 2. Transcriptional signals