Matrix Metalloproteinase-2 Is Activated During Ischemia/Reperfusion in a Model of Myocardial Infarction

Cadete, Virgilio J. J.; Arcand, Steven; Chaharyn, Bradley M.; Doroszko, Adrian; Sawicka, Jolanta; Mousseau, Darrell D.; Sawicki, Grzegorz

doi:10.1016/j.cjca.2013.03.014

Cited by 11 publications

(9 citation statements)

References 22 publications

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“…Co-localization of MMP-2 with structural proteins of thin myofilaments in hearts subjected to I/R has been established (7). Hence, MMPs may cause direct contractile dysfunction by mediating the proteolytic degradation of troponin I, myosin light chains and myosin heavy chain (3,4,6,55). In the current study we show that ischemia and reperfusion generating massive oxidative stress led to failure of cardiomyocyte contractile apparatus ( Figure 5A, B).…”

Section: Discussionsupporting

confidence: 61%

L-NAME improves doxycycline and ML-7 cardioprotection from oxidative stress

et al. 2018

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Matrix metalloproteinase-2 (MMP-2) mediated degradation of myosin light chain 1 (MLC1) and troponin I (TnI) contributes to myocardial ischemia/reperfusion (I/R) injury. Modifications of MLC1 triggered by oxidative stress are mediated by myosin light chain kinase (MLCK), nitric oxide synthase (NOS), and MMP-2. Previous studies have shown that inhibiting both MLCK and MMP-2 protects against I/R injury. Here, we hypothesized that the addition of NOS inhibitor (L-NAME) at subprotective concentration to the mixture of subprotective concentrations of ML-7 and doxycycline (Doxy), will increase a synergistic cardioprotection of Doxy and ML-7 during I/R. Isolated rat hearts were subjected to global ischemia without or with administration of the mixture of inhibitors. Markers of I/R injury were measured in hearts and coronary effluents. Addition of L-NAME to the mixture of Doxy and ML-7 led to full recovery of heart contractility in comparison to combination of Doxy and ML-7. Improved heart contractility was associated with reduced degradation of TnI and MLC1. The combined administration of NOS, MMP-2 and MLCK inhibitors provides a novel strategy to protect heart from I/R injury.

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Section: Discussionsupporting

confidence: 61%

L-NAME improves doxycycline and ML-7 cardioprotection from oxidative stress

et al. 2018

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“…Gelatin zymography was performed as previously described [ 11 , 27 ]. After electrophoresis, gels were scanned and MMP levels were measured using Quantity One 4.6 software (Bio-Rad, Hercules, CA).…”

Section: Methodsmentioning

confidence: 99%

Protection of the Transplant Kidney from Preservation Injury by Inhibition of Matrix Metalloproteinases

Möser¹,

Arcand

Lin

et al. 2016

PLoS ONE

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BackgroundMatrix metalloproteinases (MMPs), particularly MMP-2 and MMP-9, play an important role in ischemic injury to the heart, yet it is not known if these MMPs are involved in the injury that occurs to the transplant kidney. We therefore studied the pharmacologic protection of transplant kidneys during machine cold perfusion.MethodsHuman kidney perfusates were analyzed for the presence of injury markers such as cytochrome c oxidase, lactate dehydrogenase, and neutrophil-gelatinase associated lipocalin (NGAL), and MMP-2 and MMP-9 were measured. The effects of MMP inhibitors MMP-2 siRNA and doxycycline were studied in an animal model of donation after circulatory determination of death (DCDD).ResultsMarkers of injury were present in all analyzed perfusates, with higher levels seen in perfusates from human kidneys donated after controlled DCDD compared to brain death and in perfusate from kidneys with delayed graft function. When rat kidneys were perfused at 4°C for 22 hours with the addition of MMP inhibitors, this resulted in markedly reduced levels of MMP-2, MMP-9 and analyzed injury markers.ConclusionsBased on our study, MMPs are involved in preservation injury and the supplementation of preservation solution with MMP inhibitors is a potential novel strategy in protecting the transplant kidney from preservation injury.

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“…In our previous studies we also showed that both hearts [13] and kidneys [12] subjected to ischemia showed an increased activity of matrix metalloproteinase-2. Furthermore, we showed that inhibition of MMP activity by pharmacological agents protects kidneys from cold perfusion injury.…”

Section: Discussionmentioning

confidence: 68%

“…In this study, we focused on the changes observed in the proteome of kidney subjected to ischemia during machine cold perfusion. The oxidative stress of the graft during ischemia and reperfusion leads to an increased activity of matrix metalloproteinases (MMPs) [12,13], and MMPs, in turn, are able to degrade intra-and extracellular proteins [14] (causing the changes of protein content in kidneys) leading to organ injury and dysfunction,. Therefore, the main aim of the current study was to better describe the nephroprotective activity of doxycycline (MMPs inhibitor) during ex vivo kidney cold perfusion in a rat model.…”

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confidence: 99%

Protection of the transplant kidney during cold perfusion with doxycycline: proteomic analysis in a rat model

Möser

Sawicka

et al. 2020

Proteome Sci

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Background: It has been previously shown that doxycycline (Doxy) protects the kidney from preservation injury by inhibition of matrix metalloproteinase. However, the precise molecular mechanism involved in this protection from injury is not known. We used a pharmaco-proteomics approach to identify potential molecular targets associated with kidney preservation injury.Methods: Rat kidneys were cold perfused with or without doxycycline (Doxy) for 22 h. Kidneys perfusates were analyzed for the presence of injury markers such as lactate dehydrogenase (LDH), and neutrophil-gelatinase associated lipocalin (NGAL). Proteins extracted from kidney tissue were analyzed by 2-dimensional gel electrophoresis. Proteins of interest were identified by mass spectrometry. Results: Triosephosphate isomerase, PGM, dihydropteridine reductase-2, pyridine nucleotide-disulfide oxidoreductase, phosphotriesterase-related protein, and aminoacylase-1A were not affected by cold perfusion. Perfusion with Doxy increased their levels. N(G),N(G)-dimethylarginine dimethylaminohydrolase and phosphoglycerate kinase 1 were decreased after cold perfusion. Perfusion with Doxy led to an increase in their levels.Conclusions: This study revealed specific metabolic enzymes involved in preservation injury and in the mechanism whereby Doxy protects the kidney against injury during cold perfusion.

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Matrix Metalloproteinase-2 Is Activated During Ischemia/Reperfusion in a Model of Myocardial Infarction

Cited by 11 publications

References 22 publications

L-NAME improves doxycycline and ML-7 cardioprotection from oxidative stress

L-NAME improves doxycycline and ML-7 cardioprotection from oxidative stress

Protection of the Transplant Kidney from Preservation Injury by Inhibition of Matrix Metalloproteinases

Protection of the transplant kidney during cold perfusion with doxycycline: proteomic analysis in a rat model

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