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P33 Pharmacological stimulation of HIF signalling as a potential treatment approach for the type 2 diabetic heart
  1. MdL Sousa Fialho,
  2. M Kerr,
  3. MS Dodd,
  4. C Montes Aparicio,
  5. DJ Tyler,
  6. LC Heather
  1. Department of Physiology, Anatomy and Genetics, University of Oxford


Introduction In response to ischemia, type 2 diabetic hearts are less able to upregulate anaerobic glycolysis and show poorer contractile function. Pharmacological activation of Hypoxia-Inducible Factor (HIF) may be beneficial for the diabetic heart, as it may promote glycolysis, improve function and tolerance of ischaemia.

Methods Control and type 2 diabetic rats were given five oral doses (5 mg/kg daily) of PHD-selective HIF activator BAY85–3934. Hearts were perfused ex vivo and subjected to low-flow (0.35 ml/min/gww) ischaemia-reperfusion (IR). Glycolysis, palmitate oxidation and function were measured throughout. Mitochondrial oxidation was measured in isolated mitochondria using a Clark-type electrode.

Results Diabetic hearts showed decreased rate-pressure product following ischaemia-reperfusion. Pre-treatment with BAY85–3934 resulted in increased glycolytic rate in diabetic hearts, paired with improved functional recovery post-IR. BAY85–3934 treated diabetic rats showed increased hematocrit, indicating systemic activation of HIF signalling. Blood glucose levels remained unchanged with treatment despite changes in cardiac glycolytic rate.

Conclusion This study has shown that treatment with HIF activators may provide a novel avenue to improve metabolism and functional recovery in the diabetic heart following ischaemia-reperfusion.

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