Matrix metalloproteinase inhibition protects CyPD knockout mice independently of RISK/mPTP signalling: a parallel pathway to protection.
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.
The Hatter Cardiovascular Institute, Institute of Cardiovascular Medicine, University College London, London, UK.
Robert M
RM
Bell
Suma P
SP
Kunuthur
Cara
C
Hendry
Damian
D
Bruce-Hickman
Sean
S
Davidson
Derek M
DM
Yellon
D000818:Animals; D015153:Blotting, Western; D000081406:Peptidyl-Prolyl Isomerase F; D021983:Cyclophilins / Q000502:physiology*; D048049:Extracellular Signal-Regulated MAP Kinases / Q000378:metabolism*; D006877:Hydroxamic Acids; D007211:Indoles / Q000627:therapeutic use*; D008297:Male; D061965:Matrix Metalloproteinase Inhibitors / Q000627:therapeutic use*; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D033681:Mitochondrial Membrane Transport Proteins / Q000378:metabolism*; D000083162:Mitochondrial Permeability Transition Pore; D009203:Myocardial Infarction / Q000378:metabolism / Q000517:prevention & control*; D015428:Myocardial Reperfusion Injury / Q000378:metabolism / Q000517:prevention & control*; D032383:Myocytes, Cardiac / Q000378:metabolism; D010766:Phosphorylation; D051057:Proto-Oncogene Proteins c-akt / Q000378:metabolism*; D015398:Signal Transduction / Q000187:drug effects
D000081406:Peptidyl-Prolyl Isomerase F; D006877:Hydroxamic Acids; D007211:Indoles; D061965:Matrix Metalloproteinase Inhibitors; D033681:Mitochondrial Membrane Transport Proteins; D000083162:Mitochondrial Permeability Transition Pore; C000631446:PPIF protein, mouse; D051057:Proto-Oncogene Proteins c-akt; D048049:Extracellular Signal-Regulated MAP Kinases; D021983:Cyclophilins; C119203:ilomastat