Inhibition of matrix metalloproteinase-2 by PARP inhibitors

Nicolescu, Adrian C.; Holt, Andrew; Kandasamy, Arulmozhi D.; Pacher, Pál; Schulz, Richard

doi:10.1016/j.bbrc.2009.07.080

Cited by 39 publications

(36 citation statements)

References 39 publications

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“…We previously used a less selective antagonist of PARP-1, namely PHE, and observed analogous results on the rat isolated spinal cord (Kuzhandaivel et al 2010b). Since PJ 34 is reported to be also an inhibitor of metalloproteinases (Nicolescu et al 2009), we cannot exclude the possibility that this effect contributed to the current data. However, metalloproteinases comprise a large family with contrasting roles during the post-traumatic phase of spinal cord injury (Agrawal et al 2008), making it difficult to identify if anyone of them might have been involved in the neuroprotective action exerted by PJ 34.…”

Section: Neuroprotection By Pj 34supporting

confidence: 56%

Effect of the PARP-1 Inhibitor PJ 34 on Excitotoxic Damage Evoked by Kainate on Rat Spinal Cord Organotypic Slices

Mazzone

Nistri

2010

Cell Mol Neurobiol

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Excitotoxicity triggered by over-activation of glutamate receptors is thought to be an early mechanism of extensive neuronal death with consequent loss of function following lesion of spinal networks. One important process responsible for excitotoxic death is 'parthanatos' caused by hyperactivation of poly(ADP-ribose) polymerase (PARP) enzyme 1. Using rat organotypic spinal slices as in vitro models, the present study enquired if 2-(dimethylamino)-N-(5,6-dihydro-6-oxophenanthridin-2yl)acetamide (PJ 34), a pharmacological inhibitor of PARP-1, could counteract the excitotoxic damage evoked by transient application (1 h) of kainate, a potent analogue of glutamate. Kainate induced dose-dependent (1 μM threshold) neuronal loss (without damage to astrocytes) detected 24 h later via a PARP-1 dependent process that had peaked at 4 h after washout kainate. All spinal regions (ventral, central and dorsal) were affected, even though the largest damage was found in the dorsal area. Whereas PJ 34 did not protect against a large concentration (100 μM) of kainate, it significantly inhibited neuronal losses evoked by 10 μM kainate as long as it was co-applied with this glutamate agonist. When the application of PJ 34 was delayed to the washout time, neuroprotection was weak and regionally restricted. These data suggest that kainate-induced parthanatos developed early and was prevented by PJ 34 only when it was co-applied together with excitotoxic stimulus. Our results highlight the difficulty to arrest parthanatos as a mechanism of spinal neuron death in view of its low threshold of activation by kainate, its widespread distribution, and relatively fast development.

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Section: Neuroprotection By Pj 34supporting

confidence: 56%

Effect of the PARP-1 Inhibitor PJ 34 on Excitotoxic Damage Evoked by Kainate on Rat Spinal Cord Organotypic Slices

Mazzone

Nistri

2010

Cell Mol Neurobiol

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“…This concentration of o -phenanthroline inhibits MMP-2 activity under similar in vitro conditions29. The samples were denatured with 2× urea sample buffer (8 mol/L urea, 2 mol/L thiourea, 3% SDS, 75 mmol/L DTT, 0.03% bromophenol blue, and 0.05 mol/L Tris-HCl, pH 6.8) at 60°C for 10 min, and the proteins were electrophoresed by 1% SDS-agarose and stained with Coomassie brilliant blue.…”

Section: Methodsmentioning

confidence: 84%

Titin is a Target of Matrix Metalloproteinase-2

et al. 2010

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Background-Titin is the largest mammalian (Ϸ3000 to 4000 kDa) and myofilament protein that acts as a molecular spring in the cardiac sarcomere and determines systolic and diastolic function. Loss of titin in ischemic hearts has been reported, but the mechanism of titin degradation is not well understood. Matrix metalloproteinase-2 (MMP-2) is localized to the cardiac sarcomere and, on activation in ischemia/reperfusion injury, proteolyzes specific myofilament proteins. Here we determine whether titin is an intracellular substrate for MMP-2 and if its degradation during ischemia/reperfusion contributes to cardiac contractile dysfunction. Methods and Results-Immunohistochemistry and confocal microscopy in rat and human hearts showed discrete colocalization between MMP-2 and titin in the Z-disk region of titin and that MMP-2 is localized mainly to titin near the Z disk of the cardiac sarcomere. Both purified titin and titin in skinned cardiomyocytes were proteolyzed when incubated with MMP-2 in a concentration-dependent manner, and this was prevented by MMP inhibitors. Isolated rat hearts subjected to ischemia/reperfusion injury showed cleavage of titin in ventricular extracts by gel electrophoresis, which was confirmed by reduced titin immunostaining in tissue sections. Inhibition of MMP activity with ONO-4817 prevented ischemia/reperfusion-induced titin degradation and improved the recovery of myocardial contractile function. Titin degradation was also reduced in hearts from MMP-2 knockout mice subjected to ischemia/reperfusion in vivo compared with wild-type controls. Conclusion-MMP-2 localizes to titin at the Z-disk region of the cardiac sarcomere and contributes to titin degradation in myocardial ischemia/reperfusion injury. Key Words: contractile dysfunction Ⅲ ischemia Ⅲ matrix metalloproteinase-2 Ⅲ sarcomere Ⅲ titin M atrix metalloproteinase-2 (MMP-2) is a zinc-dependent protease that is best known for its ability to degrade the extracellular matrix in both physiological and pathological conditions. MMP-2 is synthesized as a zymogen by a variety of cells, including cardiac myocytes, and is activated either by proteases 1 (such as by action of or by posttranslational modifications to the full-length enzyme caused by enhanced oxidative stress. For example, peroxynitrite, which is generated in early reperfusion after ischemia, 2 directly activates several MMPs, 3 including MMP-2, 4 via a nonproteolytic mechanism involving the S-glutathiolation of a critical propeptide cysteine in its autoinhibitory domain. Ediotrial see p 2002 Clinical Perspective on p 2047MMPs are best recognized for their role in tissue remodeling by proteolyzing various components of the extracellular matrix in both health and disease, ie, in angiogenesis, embryogenesis, wound healing, 5 atherosclerosis, 6 aortic aneurysm, 7 and myocardial infarction. 8 More recent studies, however, show that MMP-2 is involved in several acute biological processes independently of its actions on extracellular matrix proteins. This includes platelet activati...

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“…A role for PARP1 overactivation in neuronal death is supported by studies demonstrating the neuroprotective effects of PARP1 inhibitors after stroke (Moroni and Chiarugi, 2009). However, some PARP1 inhibitors also inhibit MMP-2 (Nicolescu et al, 2009). Thus, the neuroprotective effects of PARP inhibitors may in part be mediated by inhibition of MMP-2.…”

Section: Discussionmentioning

confidence: 99%

Increased intranuclear matrix metalloproteinase activity in neurons interferes with oxidative DNA repair in focal cerebral ischemia

Yang

Candelario‐Jalil

Thompson

et al. 2009

Journal of Neurochemistry

112

119

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Degradation of the extracellular matrix by elevated matrix metalloproteinase (MMP) activity following ischemia/reperfusion is implicated in blood–brain barrier disruption and neuronal death. In contrast to their characterized extracellular roles, we previously reported that elevated intranuclear MMP-2 and -9 (gelatinase) activity degrades nuclear DNA repair proteins and promotes accumulation of oxidative DNA damage in neurons in rat brain at 3-h reperfusion after ischemic stroke. Here, we report that treatment with a broad-spectrum MMP inhibitor significantly reduced neuronal apoptosis in rat ischemic hemispheres at 48-h reperfusion after a 90-min middle cerebral artery occlusion (MCAO). Since extracellular gelatinases in brain tissue are known to be neurotoxic during acute stroke, the contribution of intranuclear MMP-2 and -9 activities in neurons to neuronal apoptosis has been unclear. To confirm and extend our in vivo observations, oxygen–glucose deprivation (OGD), an in vitro model of ischemia/reperfusion, was employed. Primary cortical neurons were subjected to 2-h OGD with reoxygenation. Increased intranuclear gelatinase activity was detected immediately after reoxygenation onset and was maximal at 24 h, while extracellular gelatinase levels remained unchanged. We detected elevated levels of both MMP-2 and -9 in neuronal nuclear extracts and gelatinase activity in neurons co-localized primarily with MMP-2. We found a marked decrease in PARP1, XRCC1, and OGG1, and decreased PARP1 activity. Pretreatment of neurons with selective MMP-2/9 inhibitor II significantly decreased gelatinase activity and downregulation of DNA repair enzymes, decreased accumulation of oxidative DNA damage, and promoted neuronal survival after OGD. Our results confirm the nuclear localization of gelatinases and their nuclear substrates observed in an animal stroke model, further supporting a novel role for intranuclear gelatinase activity in an intrinsic apoptotic pathway in neurons during acute stroke injury.

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Inhibition of matrix metalloproteinase-2 by PARP inhibitors

Cited by 39 publications

References 39 publications

Effect of the PARP-1 Inhibitor PJ 34 on Excitotoxic Damage Evoked by Kainate on Rat Spinal Cord Organotypic Slices

Effect of the PARP-1 Inhibitor PJ 34 on Excitotoxic Damage Evoked by Kainate on Rat Spinal Cord Organotypic Slices

Titin is a Target of Matrix Metalloproteinase-2

Increased intranuclear matrix metalloproteinase activity in neurons interferes with oxidative DNA repair in focal cerebral ischemia

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