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Increasing cardiac pyruvate dehydrogenase flux during chronic hypoxia improves acute hypoxic tolerance

Handzlik, Michal; Constantin-Teodosiu, Dumitru; Greenhaff, Paul L.; Cole, Mark

Authors

Michal Handzlik

Dumitru Constantin-Teodosiu tim.constantin@nottingham.ac.uk

MARK COLE Mark.Cole@nottingham.ac.uk
Assistant Professor



Abstract

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 30min of hypoxia, and lost 80% of prehypoxic function (p=0.001), with only 27% recovery of pre-hypoxic function with 30min of re-oxygenation (p=0.046). Activation of the PDC with infusion of 1mM dicholorocacetate (DCA) during hypoxia and re-oxygenation did not alter function. Acute hypoxic tolerance was assessed in hearts of mice housed in hypoxia for 3wks. 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, 70mg/kg/day) 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.

Journal Article Type Article
Publication Date Aug 1, 2018
Journal The Journal of Physiology
Print ISSN 0022-3751
Electronic ISSN 1469-7793
Publisher Wiley
Peer Reviewed Peer Reviewed
Volume 596
Issue 15
Pages 3357-3369
APA6 Citation Handzlik, M., Constantin-Teodosiu, D., Greenhaff, P. L., & Cole, M. (2018). Increasing cardiac pyruvate dehydrogenase flux during chronic hypoxia improves acute hypoxic tolerance. Journal of Physiology, 596(15), 3357-3369. https://doi.org/10.1113/JP275357
DOI https://doi.org/10.1113/JP275357
Keywords Heart, Hypoxia, Metabolism, Pyruvate Dehydrogenase Complex
Publisher URL http://onlinelibrary.wiley.com/doi/10.1113/JP275357/full
Copyright Statement Copyright information regarding this work can be found at the following address: http://creativecommons.org/licenses/by/4.0

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Copyright Statement
Copyright information regarding this work can be found at the following address: http://creativecommons.org/licenses/by/4.0





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