Journal
JOURNAL OF PHYSIOLOGY-LONDON
Volume 596, Issue 15, Pages 3357-3369Publisher
WILEY
DOI: 10.1113/JP275357
Keywords
heart; hypoxia; metabolism; pyruvate dehydrogenase complex
Categories
Funding
- University of Nottingham
- Biotechnology and Biological Sciences Research Council (BBSRC) [BB/F016956/1]
- BBSRC [BB/F016956/1] Funding Source: UKRI
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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.
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