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Activating hypoxia inducible factor in the heart by genetic inactivation of von Hippel Lindau protein reduces myocardial infarct size
  1. S Lim1,
  2. SG Ong1,
  3. DH Shukla2,
  4. P Maxwell2,
  5. DJ Hausenloy1,
  6. DM Yellon1
  1. 1The Hatter Cardiovascular Institute, University College London Hospital and Medical School, London, UK,
  2. 2Centre for Cell Signalling and Molecular Genetics, University College London, London, UK

Abstract

Introduction The activation of hypoxia inducible factor 1 (HIF-1) has been demonstrated to be cardioprotective. Under normoxic conditions von Hippel Lindau (VHL) protein assists in the degradation of HIF-1. We hypothesised that the activation of HIF-1 within the heart by the genetic inactivation of cardiac-specific VHL reduces myocardial infarct size.

Methods We used conditional cardiac-specific VHL knockout mice that express an inducible Cre recombinase transgene to delete the VHL-floxed gene within the heart in an acute manner following tamoxifen induction (4 mg/mouse per day for 5 days by intraperitoneal injection). Conditional cardiac-specific VHL knockout mice and littermate controls were then subjected to in-situ 30 minutes left anterior coronary artery ischaemia followed by 120 minutes of myocardial reperfusion, at the end of which myocardial infarct size was determined by tetrazolium staining.

Results Using immunostaining techniques, the cardiac-specific ablation of VHL was demonstrated to activate myocardial HIF-1 markedly when compared with control hearts in which no HIF-1 activation was observed. The activation of myocardial HIF-1 arising from the genetic inactivation of VHL resulted in a smaller myocardial infarct size when compared with control (30.8 ± 8.3% in VHL knockout versus 62.7 ± 4.1% in control; p<0.05; N  =  5–6 animals per group).

Conclusion The acute activation of the HIF-1 within the heart from the genetic inactivation of cardiac-specific VHL reduces myocardial infarct size.

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