Abstract
Key points The cardiac metabolic reprogramming seen in heart diseases such as myocardial infarction and hypertrophy shares similarities with that seen in chronic hypoxia, but understanding of how the hypoxic heart responds to further hypoxic challenge – hypoxic tolerance – is limited.The pyruvate dehydrogenase complex serves to control irreversible decarboxylation of pyruvate within mitochondria, and is a key regulator of substrate metabolism, potentially regulating hypoxic tolerance.Acute activation of the pyruvate dehydrogenase complex did not improve cardiac function during acute hypoxia; however, simultaneous activation of the pyruvate dehydrogenase complex during chronic hypoxic exposure improved tolerance to subsequent acute hypoxia.Activation of the pyruvate dehydrogenase complex during chronic hypoxia stockpiled cardiac acetylcarnitine, and this was used during acute hypoxia. This maintained cardiac ATP and glycogen, and improved hypoxic tolerance as a result.These findings demonstrate that pyruvate dehydrogenase complex activation can improve cardiac function under hypoxia. The pattern of metabolic reprogramming in chronic hypoxia shares similarities with that following myocardial infarction or hypertrophy; however, the response of the chronically hypoxic heart to subsequent acute injury, and the role of metabolism is not well understood. Here, we determined the myocardial tolerance of the chronically hypoxic heart to subsequent acute injury, and hypothesised that activation of a key regulator of myocardial metabolism, the pyruvate dehydrogenase complex (PDC), could improve hypoxic tolerance. Mouse hearts, perfused in Langendorff mode, were exposed to 30 min of hypoxia, and lost 80% of pre‐hypoxic function (P = 0.001), with only 51% recovery of pre‐hypoxic function with 30 min of reoxygenation (P = 0.046). Activation of the PDC with infusion of 1 mm dichloroacetate (DCA) during hypoxia and reoxygenation did not alter function. Acute hypoxic tolerance was assessed in hearts of mice housed in hypoxia for 3 weeks. Chronic hypoxia reduced cardiac tolerance to subsequent acute hypoxia, with recovery of function 22% of pre‐acute hypoxic levels vs. 39% in normoxic control hearts (P = 0.012). DCA feeding in chronic hypoxia (per os, 70 mg kg−1 day−1) doubled cardiac acetylcarnitine content, and this fell following acute hypoxia. This acetylcarnitine use maintained cardiac ATP and glycogen content during acute hypoxia, with hypoxic tolerance normalised. In summary, chronic hypoxia renders the heart more susceptible to acute hypoxic injury, which can be improved by activation of the PDC and pooling of acetylcarnitine. This is the first study showing functional improvement of the chronically hypoxic heart with activation of the PDC, and offers therapeutic potential in cardiac disease with a hypoxic component.
Highlights
Altered cardiac energy metabolism is an integral component of the aetiology and progression of heart failure
Cardiac function fell steadily throughout acute hypoxia, with a 60% fall in developed pressure (DP) (P = 0.003) and an 80% fall in Rate pressure product (RPP) after 30 min (P = 0.001)
In contrast to the 4-fold rise in pyruvate dehydrogenase complex (PDC) activity with DCA infusion throughout acute hypoxia and reoxygenation, acetylcarnitine only rose by 71% in acute hypoxia compared to control hearts, and was 80% higher by the end of reoxygenation
Summary
Altered cardiac energy metabolism is an integral component of the aetiology and progression of heart failure. We have developed and characterised a moderate hypoxic protocol (Heather et al 2012; Cole et al 2016; Mansor et al 2016), which involves a period of acclimation similar to that employed by humans in transition to high altitude (Holloway et al 2011) In this model, baseline myocardial function was unaffected, underpinned by extensive metabolic reprogramming, but disruption of this apparent adaptation resulted in cardiac dysfunction (Cole et al 2016; Mansor et al 2016). More detailed information on cardiac responses to hypoxia is needed in order to potentially offer therapies for cardiac disease by identifying intermediate metabolic targets
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