Tissue inhibitor of metalloproteinases‐3 and matrix metalloproteinase‐3 regulate neuronal sensitivity to doxorubicin‐induced apoptosis

Wetzel, Monica; Rosenberg, Gary A.; Cunningham, Lee Anna

doi:10.1046/j.1460-9568.2003.02838.x

Cited by 85 publications

(90 citation statements)

References 57 publications

(77 reference statements)

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“…As illustrated in the merged images, cortical neurons uniformly express both Fas and FasL in culture. These data are consistent with previous reports demonstrating that Fas 2,6,25,27 and FasL 2,25,27 are constitutively expressed by cultured rodent cortical neurons, and that expression of these death receptors and their ligands alone is not sufficient to induce neuronal death.…”

Section: Resultssupporting

confidence: 93%

“…We previously demonstrated that rat cortical neurons constitutively express TIMP-3 mRNA and functional protein in culture, 25 and have previously reported TIMP-3 mRNA expression by mouse cortical neurons in culture. 27 Cultures were continuously exposed to both inhibitors for 24 h after return to normoxia, followed by immunofluorescence staining for NeuN and assessment of neuronal survival.…”

Section: Resultsmentioning

confidence: 88%

“…To determine whether Fas activation is required for OGDinduced neuronal cell death, as previously demonstrated for doxorubicin-induced cell death, 25 we incubated wild-type neuronal cultures with a function-blocking anti-FasL antibody or with an Fc fragment of human IgG1 fused to the ectodomain of Fas (Fas-Fc), during and after exposure to OGD. These inhibitors act as decoy receptors to block the interaction of endogenous FasL with its receptor.…”

Section: Resultsmentioning

confidence: 99%

“…19 TIMP-3 has been shown to play a role in the regulation of receptor-mediated cell death in various cell types through inhibition of metalloproteinase activity and stabilization of cell-surface death receptors. [20][21][22][23][24][25] Within the CNS, TIMP-3 is transiently expressed in embryonic cerebral cortex during the period of naturally occurring programmed cell death 26 and is upregulated and colocalized with Fas in penumbral cortical neurons undergoing apoptosis following ischemia in the adult. 9 In culture, TIMP-3 is constitutively expressed by embryonic cortical neurons 25,27 and is necessary for Fas-mediated apoptosis induced by the chemotherapeutic drug, doxorubicin.…”

mentioning

confidence: 99%

“…9 In culture, TIMP-3 is constitutively expressed by embryonic cortical neurons 25,27 and is necessary for Fas-mediated apoptosis induced by the chemotherapeutic drug, doxorubicin. 25 Here, we report that TIMP-3 also acts to facilitate Fas-mediated neuronal cell death following ischemia. We compared neuronal cell death in cortical cultures established from wildtype versus timp-3 À/À mice following exposure to oxygenglucose deprivation (OGD) in vitro and following mild focal cerebral ischemia in vivo.…”

mentioning

confidence: 99%

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Tissue inhibitor of metalloproteinases-3 facilitates Fas-mediated neuronal cell death following mild ischemia

Wetzel

Harms

et al. 2007

Cell Death Differ

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Tissue inhibitor of metalloproteinase-3 (TIMP-3) is a natural inhibitor of metalloproteinases involved in matrix degradation and ectodomain shedding of many cell-surface proteins, including death receptors and/or their ligands. In the present study, we examined the role of TIMP-3 in Fas-mediated neuronal cell death following cerebral ischemia, using both gene deletion and pharmacological approaches. In culture, exposure of primary cortical neurons to 2 h of oxygen-glucose deprivation (OGD) resulted in delayed neuronal cell death that was dependent on activation of the death receptor, Fas. Cortical cultures derived from timp-3 À/À mice displayed partial resistance against OGD-induced neuronal cell death and also displayed increased shedding of Fas ligand (FasL) into the culture media, compared to wild-type control cultures. Both the increased neuroprotection and increased FasL shedding in timp-3 À/À cultures were reversed by addition of exogenous metalloproteinase inhibitors, recombinant TIMP-3 or GM6001. In vivo, timp-3 À/À mice showed marked resistance to a brief (30 min) middle cerebral artery occlusion (MCAO), but were not protected against more severe lesions induced by 90 min of MCAO. These studies demonstrate that TIMP-3 facilitates Fas-mediated neuronal cell death following OGD and plays a pro-apoptotic role in mild cerebral ischemia.

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Section: Resultssupporting

confidence: 93%

Section: Resultsmentioning

confidence: 88%

Section: Resultsmentioning

confidence: 99%

mentioning

confidence: 99%

mentioning

confidence: 99%

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Tissue inhibitor of metalloproteinases-3 facilitates Fas-mediated neuronal cell death following mild ischemia

Wetzel

Harms

et al. 2007

Cell Death Differ

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Dynamic shimming of the human brain at 7 T

Juchem

Nixon

Diduch

et al. 2010

Concepts Magn Reson

168

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Dynamic shim updating (DSU) of the zero-to second-order spherical harmonic field terms has previously been shown to improve the magnetic field homogeneity in the human brain at 4 Tesla. The increased magnetic field inhomogeneity at 7 Tesla can benefit from inclusion of third-order shims during DSU. However, pulsed higher-order shims can generate a multitude of temporally varying magnetic fields arising from eddy-currents that can strongly degrade the magnetic field homogeneity.The first realization of zero-to third-order DSU with full preemphasis and B 0 compensation enabled improved shimming of the human brain at 7 Tesla not only in comparison with global (i.e. static) shimming, but also when compared to state-of-the-art zero-to second-order DSU. Temporal shim-to-shim interactions were measured for each of the 16 zero-to third-order shim coils along 1D column projections on a spherical phantom. The decomposition into up to 3 exponentials allowed full preemphasis and B 0 compensation of all 16 shims covering 67 potential shim-to-shim interactions. Despite the significant improvements achievable with DSU, the magnetic field homogeneity is still not perfect even when updating all zero-through third-order shims. This is because DSU is still inherently limited by the shallowness of the low order spherical harmonic fields and their inability to compensate the higher-order inhomogeneities encountered in vivo. However, DSU maximizes the usefulness of conventional shim coil systems and provides magnetic field homogeneity that is adequate for a wide range of applications.

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Doxorubicin‐Induced Cardiomyopathy in Children

Mancilla

Iskra

Aune

2019

Comprehensive Physiology

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Doxorubicin-induced cardiotoxicity in childhood cancer survivors is a growing problem. The population of patients at risk for cardiovascular disease is steadily increasing, as five-year survival rates for all types of childhood cancers continue to improve. Doxorubicin affects the developing heart differently from the adult heart and in a subset of exposed patients, childhood exposure leads to late, irreversible cardiomyopathy. Notably, the prevalence of late-onset toxicity is increasing in parallel with improved survival. By the year 2020, it is estimated that there will be 500,000 childhood cancer survivors and over 50,000 of them will suffer from doxorubicin-induced cardiotoxicity. The majority of the research to-date, concentrated on childhood cancer survivors, has focused mostly on clinical outcomes through well-designed epidemiological and retrospective cohort studies. Preclinical studies have elucidated many of the cellular mechanisms that elicit acute toxicity in cardiomyocytes. However, more research is needed in the areas of early-and late-onset cardiotoxicity and more importantly improving the scientific understanding of how other cells present in the cardiac milieu are impacted by doxorubicin exposure. The overall goal of this review is to succinctly summarize the major clinical and preclinical studies focused on doxorubicin-induced cardiotoxicity. As the prevalence of patients affected by doxorubicin exposure continues to increase, it is imperative that the major gaps in existing research are identified and subsequently utilized to develop appropriate research priorities for the coming years. Well-designed preclinical research models will enhance our understanding of the pathophysiology of doxorubicin-induced cardiotoxicity and directly lead to better diagnosis, treatment, and prevention.

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Tissue inhibitor of metalloproteinases‐3 and matrix metalloproteinase‐3 regulate neuronal sensitivity to doxorubicin‐induced apoptosis

Cited by 85 publications

References 57 publications

Tissue inhibitor of metalloproteinases-3 facilitates Fas-mediated neuronal cell death following mild ischemia

Tissue inhibitor of metalloproteinases-3 facilitates Fas-mediated neuronal cell death following mild ischemia

Dynamic shimming of the human brain at 7 T

Doxorubicin‐Induced Cardiomyopathy in Children

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