| Matrix metalloproteinase inhibition protects CyPD knockout mice independently of RISK/mPTP signalling: a parallel pathway to protection. | |
| | |
MedLine Citation:
|
PMID: 23361433 Owner: NLM Status: In-Data-Review |
Abstract/OtherAbstract:
|
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. |
| | |
Authors:
|
Robert M Bell; Suma P Kunuthur; Cara Hendry; Damian Bruce-Hickman; Sean Davidson; Derek M Yellon |
Related Documents
:
|
23052973 - Cardiac magnetic resonance imaging of rapid vcam-1 up-regulation in myocardial ischemia... 19761983 - Increasing benefit from revascularization is associated with increasing amounts of myoc... 16251233 - Prognostic value of systolic mitral annular velocity measured with doppler tissue imagi... |
Publication Detail:
|
Type: Journal Article 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: - Revised Date: - |
Medline Journal Info:
|
Nlm Unique ID: 0360342 Medline TA: Basic Res Cardiol Country: Germany |
Other Details:
|
Languages: eng Pagination: 331 Citation Subset: IM |
Affiliation:
|
The Hatter Cardiovascular Institute, Institute of Cardiovascular Medicine, University College London, 67 Chenies Mews, London, WC1E 6HX, UK. |
Export Citation:
|
APA/MLA Format Download EndNote Download BibTex |
| MeSH Terms | |
Descriptor/Qualifier:
|
|
From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine
Previous Document: Large balloon dilation for the treatment of recurrent bile duct stones prevents short-term recurrenc...
Next Document: Efficacy of herpes virus helicase-primase inhibitor, ASP2151, for treating herpes simplex keratitis ...