Document Detail

BAS/BSCR33 Cardioprotection by hypoxia-inducible factor-1{alpha}: underlying beneficial effects on mitochondrial function.
MedLine Citation:
PMID:  20801826     Owner:  NLM     Status:  In-Data-Review    
Introduction Activation of hypoxia-inducible factor-1alpha (HIF-1alpha) protects the heart from ischaemia-reperfusion injury, although the underlying mechanisms are unclear. We hypothesised that HIF-1alpha-induced cardioprotection is mediated by beneficial effects on mitochondrial function. Methods and results Two different experimental models of HIF-1alpha activation were used: (1) pharmacological inhibition of proline hydroxylase (PHD) and (2) genetic inactivation of von Hippel-Lindau (VHL), proteins responsible for HIF-1alpha degradation under normoxic conditions. A single dose (3 mg/kg) of the PHD inhibitor (GSK0360A or PHDi), administered by oral gavage 4 h before ex vivo myocardial infarction, reduced myocardial infarct size (percentage of the area at risk) in male Sprague-Dawley rats (30.6%+/-2.9% PHDi vs 44.2%+/-2.9%; p<0.5; N>5). Next, conditional cardiac-specific VHL knockout mice (VHL-KO) that express an inducible Cre-recombinase transgene to delete the VHL-floxed gene within the heart following tamoxifen induction, expressed higher levels of HIF-1 in the heart as assessed by immunostaining. The activation of myocardial HIF-1 resulted in a smaller myocardial infarct size in comparison with the littermate control (29.1%+/-4.7% in VHL-KO vs 52.5%+/-3.3% in control; p<0.05; N>5/group). In VHL-KO cardiomyocytes subjected to simulated ischaemia-reperfusion injury (SIRI) (120 min ischaemia and 15 min reperfusion, the production of reactive oxygen species (ROS) (measured by reduced Mitotracker Red fluorescence)(1.0%+/-0.1-fold increase in VHL-KO vs 1.3%+/-0.2-fold increase in control; p<0.05; N>3 experiments each with 40 cells) and mitochondrial permeability transition pore (mPTP) opening sensitivity was reduced (measured by TMRM fluorescence) (1.1%+/-0.1 fold increase in VHL-KO vs 1.4%+/-0.1 fold increase in control; p<0.05; N>3 experiments each with 40 cells). Conclusions HIF-1alpha activation by genetic deletion of VHL or pharmacological inhibition of PHD, is cardioprotective and this protective effect can be attributed in part to beneficial effects on the mitochondria.
S-G Ong; S Y Lim; L Theodorou; D H Shukla; P H Maxwell; D M Yellon; D J Hausenloy
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Publication Detail:
Type:  Journal Article    
Journal Detail:
Title:  Heart (British Cardiac Society)     Volume:  96     ISSN:  1468-201X     ISO Abbreviation:  Heart     Publication Date:  2010 Sep 
Date Detail:
Created Date:  2010-08-30     Completed Date:  -     Revised Date:  -    
Medline Journal Info:
Nlm Unique ID:  9602087     Medline TA:  Heart     Country:  England    
Other Details:
Languages:  eng     Pagination:  e22     Citation Subset:  AIM; IM    
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