The role of dichloroacetate in improving acute hypoxic tolerance and cardiac function: translation to failing hearts?

Cardiac metabolism depends on a high rate of ATP production to maintain its myocardial pump function. Under physiological conditions, more than 70% of ATP generated in the heart is derived from β-oxidation of fatty acids (FAs) in the mitochondria. In heart failure, the switch from FA to carbohydrate metabolism as the dominant energy substrate is indicative of pathological conditions. This insufficiency of energy production and metabolic dysfunction is commonly seen in hypoxic and ischaemic conditions such as post-myocardial infarction (MI) and failing hearts. Both hypoxic and ischaemic cardiac tissues undergo similar metabolic remodelling processes where the over-reliance on anaerobic glycolysis contributes to cardiac dysfunction. Thus, understanding the molecular signals that drive this metabolic switch is crucial for identifying novel therapeutic targets. Pyruvate dehydrogenase complex (PDC), the rate-limiting step of glucose oxidation, has been studied as a potential target because it commits pyruvate for oxidation in the mitochondria. Recent studies have led to speculation that pharmacological activation of PDC can improve cardiac function by promoting glucose oxidation. In fact, stimulation of PDC activity has been shown to decrease infarct size following MI in murine models, demonstrating the importance of proper mitochondrial function post-MI injury (Ussher et al. 2012). However, the role of PDC in metabolic dysfunction has not been well-defined and much remains to be elucidated about the role of PDC in cardiac hypoxia. In a recent study by Handzlik et al. (2018) published in this issue of The Journal of Physiology, the authors investigated the therapeutic role of dichloroacetate (DCA), a PDC stimulator, in acute and chronic hypoxic ex vivo murine models. The authors hypothesized that PDC activity would be suppressed in chronic hypoxia, reducing hypoxic tolerance in the heart. More importantly, they further hypothesized that increasing PDC activity using DCA can provoke beneficial effects in the mitochondria during chronic hypoxia. Cardiac function was measured continuously using a polyethylene balloon in hearts perfused at one-fifth of normoxic levels followed by re-oxygenation to model acute hypoxic injury in 8-week-old male CD1 mice. For chronic hypoxic exposure, mice were placed in a normobaric hypoxic chamber where the fraction of inspired oxygen () was gradually reduced to 11% over 7 days and maintained at 11% for 14 more days. DCA was introduced into the perfusion buffer (1 mm) and the drinking water (70 mg kg−1 day−1) in the acute and chronic hypoxic settings, respectively. Detailed metabolic assays including pyruvate dehydrogenase activity, glycolytic flux and acetylcarnitine content were performed to measure changes in cardiac metabolic flux associated with hypoxia. The authors provided direct evidence that DCA treatment can preserve ATP levels and improve cardiac function following an acute hypoxic challenge in chronic hypoxic settings by possibly increasing acetylcarnitine stores to be used for maintaining the ATP pool. This represents the first study to positively correlate hypoxic tolerance with activation of PDC where DCA treatment can effectively improve cardiac function of chronically hypoxic hearts. These findings contribute towards our understanding of metabolic remodelling following chronic hypoxia that shapes subsequent hypoxic tolerance. Therapeutic targeting of PDC has been a suggested therapy for the treatment of cancer since 2007, resulting in the generation of mitochondrial pyruvate dehydrogenase kinase (PDK) inhibitors. Here, Handzlik et al. administered DCA, a direct PDK inhibitor, to enhance PDC activity and determine the impact of PDC activation on hypoxic tolerance in the myocardium. The authors reported an interesting finding where DCA treatment in mice exposed to chronic hypoxia reversed glycolytic flux similar to that of the control and increased PDC flux as evidenced by increased cardiac acetylcarnitine levels. However, this was not accompanied by changes in PDC activity. These observations may be attributed to the short half-life of DCA and can highlight the difficulty and the limitations of tracking metabolic changes in chronic hypoxic models in a timely manner. This also suggests that there may be DCA-independent effects on glucose oxidation that act to normalize the glycolytic flux in this hypoxic model. Furthermore, hypoxia is also associated with activation of multiple pathways including haem oxygenase 1 and hypoxia-inducible factor 1 (HIF-1) signalling. HIF-1 is part of a protective mechanism against hypoxia that mediates the transcription of angiogenic factors and metabolic genes encoding glucose transporters and glycolytic enzymes such as PDK (Krishnan et al. 2009). Specifically, HIF-1 was found to reduce FA oxidation by directing more FA for lipid synthesis. Interestingly, HIF-1 has been shown to be transiently involved in the early response to hypoxia and its levels have been found to normalize with sustained hypoxic conditions in beating cardiac cells as well as other tissues such as brain, liver and kidney. This suggests that HIF-1 may not be an important factor in the setting of chronic hypoxia but may help shape the acute hypoxic tolerance of chronically hypoxic murine models. Thus, future studies using DCA should consider measuring other hypoxic and oxidation markers to gain a more comprehensive understanding of the therapeutic mechanisms of DCA. Although the inclusion of measurements of glycolytic flux, lactate efflux and acetyl content accumulation was a strength of the study, assessment of the expression levels of the HIF-1/ vascular endothelial growth factor (VEGF) signalling pathway would have provided invaluable insight on the role of DCA in HIF-1 driven metabolic changes in chronically hypoxic models. While the current study successfully assessed the role of DCA as one of the key determinants in improving cardiac function in response to chronic hypoxia, many aspects of its metabolic function remain poorly understood. DCA has been previously used to favour glycolytic oxidation over FA oxidation in post-MI and ventricular fibrillation models where PDC function is impaired. DCA treatment has also been shown to reduce myocardial apoptosis and reverse mitochondrial structural abnormalities in animal models of right ventricular failure (Sun et al. 2016). These findings highlight the close association between mitochondrial metabolism and its structural remodelling in response to pathological conditions, suggesting that the therapeutic capacity of DCA treatment could have been underestimated. Future studies should include assessments of these remodelling processes to determine how mitochondrial health may shape its metabolic response to hypoxia and DCA treatment. Metabolism is also sensitive to non-pathological environmental stimuli such as regular aerobic exercise, which has been shown to increase glycolysis and oxidative metabolism. Endurance exercise training elicits long-term metabolic adaptations resulting in a significant increase in the expression levels of enzymes associated with glycolytic oxidation. Future studies should investigate the interaction between aerobic exercise and cardiac mitochondrial metabolism to examine the influence of behavioural adaptations. While the therapeutic effects of DCA depend on its ability to enter mitochondria to inhibit PDK, its short half-life is a potential limitation. Therefore, its translation to clinical settings may require a bioengineered drug delivery platform that reduces its decay time to produce sustained metabolic effects. It is also important to note other therapeutic candidates as a combination of strategies may be beneficial for treating hypoxic and ischaemic injuries. For example, there have been studies on promoting angiogenesis and metabolic therapies involving direct intravenous infusion of glucose, insulin and potassium (GIK) for ischaemic heart disease. A recent Perspectives article in The Journal of Physiology (Uddin et al. 2018), aimed to highlight the novel mechanistic role of DCA shown by Handzlik et al. (2018), also suggested future pharmacological interventions in mitochondrial metabolism to consider the ageing-dependent decline in quantity and quality of the mitochondria. This is particularly important in the setting of hypoxia and ischaemic heart disease because the risk for such cardiovascular diseases increases with age. Thus, mitochondrial health may be important to normalize for the DCA treatment to have beneficial effects in the older patient population. In conclusion, Handzlik et al. presented DCA as a potential therapeutic drug for improving acute hypoxic tolerance and cardiac function of chronically hypoxic hearts by increasing acetyl group availability. Their findings provide novel insight into the role of DCA in regulating hypoxic tolerance by minimizing cardiac ATP depletion in chronically hypoxic hearts. Although these findings highlight DCA as an emerging metabolic drug candidate for post-ischaemic injury and failing hearts, it is important to consider whether these findings have clinical relevance as hypoxia is defined as oxygen deficiency whereas ischaemia refers to inadequate blood supply resulting in lack of nutrients and poor removal of metabolic by-products. Thus, hypoxia is only responsible for a subset of physiological consequences observed in ischaemia. Lastly, the ex vivo findings observed in this study should be validated and further substantiated with in vivo models. None declared. Both authors have approved the final version of the manuscript and agree to be accountable for all aspects of the work. All persons designated as authors qualify for authorship, and all those who qualify for authorship are listed. We would like to acknowledge relevant studies on this topic that were not cited due to reference restrictions.

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