Document Detail

Matrix metalloproteinase inhibition protects CyPD knockout mice independently of RISK/mPTP signalling: a parallel pathway to protection.
MedLine Citation:
PMID:  23361433     Owner:  NLM     Status:  MEDLINE    
The mitochondrial permeability transition pore (mPTP) is widely accepted as an end-effector mechanism of conditioning protection against injurious ischaemia/reperfusion. However, death can be initiated in cells without pre-requisite mPTP opening, implicating alternate targets for ischaemia/reperfusion injury amelioration. Matrix metalloproteinases (MMP) are known to activate extrinsic apoptotic cascades and therefore we hypothesised that MMP activity represents an mPTP-independent target for augmented attenuation of ischaemia/reperfusion injury. In ex vivo and in vivo mouse hearts, we investigated whether the MMP inhibitor, ilomastat (0.25 μmol/l), administered upon reperfusion could engender protection in the absence of cyclophilin-D (CyPD), a modulator of mPTP opening, against injurious ischaemia/reperfusion. Ilomastat attenuated infarct size in wild-type (WT) animals [37 ± 2.8 to 22 ± 4.3 %, equivalent to ischaemic postconditioning (iPostC), used as positive control, 27 ± 2.1 %, p < 0.05]. Control CyPD knockout (KO) hearts had smaller infarcts than control WT (28 ± 4.2 %) and iPostC failed to confer additional protection, yet ilomastat significantly attenuated infarct size in KO hearts (11 ± 3.0 %, p < 0.001), and similar protection was also seen in isolated cardiomyocytes. Moreover, ilomastat, unlike the cyclophilin inhibitor cyclosporine-A, had no impact upon reactive oxygen species-mediated mPTP opening. While MMP inhibition was associated with increased Akt and ERK phosphorylation, neither Wortmannin nor PD98059 abrogated ilomastat-mediated protection. We demonstrate that MMP inhibition is cardioprotective, independent of Akt/ERK/CyPD/mPTP activity and is additive to the protection observed following inhibition of mPTP opening, indicative of a parallel pathway to protection in ischaemic/reperfused heart that may have clinical applicability in attenuating injury in acute coronary syndromes and deserve further investigation.
Robert M Bell; Suma P Kunuthur; Cara Hendry; Damian Bruce-Hickman; Sean Davidson; Derek M Yellon
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Publication Detail:
Type:  Journal Article; Research Support, Non-U.S. Gov't     Date:  2013-01-30
Journal Detail:
Title:  Basic research in cardiology     Volume:  108     ISSN:  1435-1803     ISO Abbreviation:  Basic Res. Cardiol.     Publication Date:  2013 Mar 
Date Detail:
Created Date:  2013-01-30     Completed Date:  2013-07-18     Revised Date:  2014-11-05    
Medline Journal Info:
Nlm Unique ID:  0360342     Medline TA:  Basic Res Cardiol     Country:  Germany    
Other Details:
Languages:  eng     Pagination:  331     Citation Subset:  IM    
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MeSH Terms
Blotting, Western
Cyclophilins / physiology*
Extracellular Signal-Regulated MAP Kinases / metabolism*
Indoles / therapeutic use*
Matrix Metalloproteinase Inhibitors / therapeutic use*
Mice, Inbred C57BL
Mice, Knockout
Mitochondrial Membrane Transport Proteins / metabolism*
Myocardial Infarction / metabolism,  prevention & control*
Myocardial Reperfusion Injury / metabolism,  prevention & control*
Myocytes, Cardiac / metabolism
Proto-Oncogene Proteins c-akt / metabolism*
Signal Transduction / drug effects
Grant Support
RG/08/015/26411//British Heart Foundation
Reg. No./Substance:
0/Indoles; 0/Matrix Metalloproteinase Inhibitors; 0/Mitochondrial Membrane Transport Proteins; 0/mitochondrial permeability transition pore; EC Proteins c-akt; EC Signal-Regulated MAP Kinases; EC 5.2.1.-/Cyclophilins; EC D; I0403ML141/ilomastat

From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine

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