p53-Regulated Increase in Oxidative-Stress–Induced Apoptosis in Fuchs Endothelial Corneal Dystrophy: A Native Tissue Model

Azizi, Behrooz; Ziaei, Alireza; Fuchsluger, Thomas Armin; Schmedt, Thore; Chen, Yuming; Jurkunas, Ula V.

doi:10.1167/iovs.11-8312

Cited by 90 publications

(95 citation statements)

References 14 publications

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“…When MN is neutralized by 2-electron reduction by NAD(P)H quinone dehydrogenase 1 (NQO1), it forms a stable hydroquinone without abnormal ROS generation. In FECD, there is decrease in Nrf2-dependent antioxidant defense shown by decreased nuclear Nrf2 translocation and the ability to upregulate antioxidant response element-dependent antioxidants, such as NQO1 (2). Due to the deficient 2-electron reductive scavenging by NQO1, it is envisaged that MN is reduced by the 1-electron pathway, causing greater internal ROS production and overwhelming the antioxidant system that is dysfunctional in FECD (35).…”

Section: Discussionmentioning

confidence: 99%

“…Cell loss in FECD has been shown to be mediated by apoptosis and specifically p53 (2,6,23). Next, we investigated whether caspase activation was involved in rosette formation, leading to endothelial cell loss.…”

Section: Mn-induced Apoptosis Is Caspase Dependent During Rosette Formentioning

confidence: 99%

“…Fuchs endothelial corneal dystrophy (FECD) leads to gradual and age-related loss of HCEnCs and leads to corneal edema and blindness (27,46). FECD affects Specifically, studies on the composition of rosettes showed overproduction of clusterin (CLU) and transforming growth factor-b-induced (TGFBI) protein, as well as increased proportion of TUNEL-positive cells adjacent to the acellular centers of the rosettes (2,22,23). Evidence indicated an underlying oxidant-antioxidant imbalance, which leads to oxidant-induced apoptosis, in FECD ex vivo and in vitro models (2,23).…”

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confidence: 99%

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Menadione-Induced DNA Damage Leads to Mitochondrial Dysfunction and Fragmentation During Rosette Formation in Fuchs Endothelial Corneal Dystrophy

Halilovic

Schmedt

Benischke

et al. 2016

Antioxidants & Redox Signaling

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Aims: Fuchs endothelial corneal dystrophy (FECD), a leading cause of age-related corneal edema requiring transplantation, is characterized by rosette formation of corneal endothelium with ensuing apoptosis. We sought to determine whether excess of mitochondrial reactive oxygen species leads to chronic accumulation of oxidative DNA damage and mitochondrial dysfunction, instigating cell death. Results: We modeled the pathognomonic rosette formation of postmitotic corneal cells by increasing endogenous cellular oxidative stress with menadione (MN) and performed a temporal analysis of its effect in normal (HCEnC, HCECi) and FECD (FECDi) cells and ex vivo specimens. FECDi and FECD ex vivo specimens exhibited extensive mtDNA and nDNA damage as detected by quantitative PCR. Exposure to MN triggered an increase in mitochondrial superoxide levels and led to mtDNA and nDNA damage, while DNA amplification was restored with NAC pretreatment. Furthermore, MN exposure led to a decrease in DCm and adenosine triphosphate levels in normal cells, while FECDi exhibited mitochondrial dysfunction at baseline. Mitochondrial fragmentation and cytochrome c release were detected in FECD tissue and after MN treatment of HCEnCs. Furthermore, cleavage of caspase-9 and caspase-3 followed MN-induced cytochrome c release in HCEnCs. Innovation: This study provides the first line of evidence that accumulation of oxidative DNA damage leads to rosette formation, loss of functionally intact mitochondria via fragmentation, and subsequent cell death during postmitotic cell degeneration of ocular tissue. Conclusion: MN induced rosette formation, along with mtDNA and nDNA damage, mitochondrial dysfunction, and fragmentation, leading to activation of the intrinsic apoptosis via caspase cleavage and cytochrome c release.

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Section: Discussionmentioning

confidence: 99%

Section: Mn-induced Apoptosis Is Caspase Dependent During Rosette Formentioning

confidence: 99%

mentioning

confidence: 99%

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Menadione-Induced DNA Damage Leads to Mitochondrial Dysfunction and Fragmentation During Rosette Formation in Fuchs Endothelial Corneal Dystrophy

Halilovic

Schmedt

Benischke

et al. 2016

Antioxidants & Redox Signaling

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“…Oxidative stress and apoptosis are reported to play a role in the development of FECD particularly in regard to accelerated corneal endothelial cell loss (Borderie et al 2000;Li et al 2001;Buddi et al 2002;Szentmáry et al 2005;Engler et al 2010;Jurkunas et al 2010;Azizi et al 2011). This may be in part due to chronic ultraviolet (UV) light exposure (Inoki et al 2004).…”

Section: Discussionmentioning

confidence: 99%

Polymorphisms of the Apoptosis-Related FAS and FAS Ligand Genes in Keratoconus and Fuchs Endothelial Corneal Dystrophy

Synowiec

Wójcik

Izdebska

et al. 2014

Tohoku J. Exp. Med.

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Keratoconus (KC) is a non-inflammatory eye disease characterized by progressive corneal thinning and asymmetrical conical protrusion of the cornea. Fuchs endothelial corneal dystrophy (FECD) is a degenerative, slowly progressive disease of the corneal endothelium that is characterized by alteration in corneal endothelial cell morphology and progressive loss of these cells. They are unrelated eye diseases that may ultimately lead to vision loss. Their pathogenesis is largely unknown, although impaired apoptosis has been suggested to be responsible for both diseases. Therefore, we studied the frequency of the c.-671A>G polymorphism of the apoptosis-related FAS gene and the c.-844T>C polymorphism of the FAS ligand (FASLG) gene in patients with FECD (221 individuals) or KC (264) and controls (300). Each polymorphism is located within the putative cis-acting element of the respective promoter. Risk of KC or FECD was estimated with unconditional multiple logistic regression with adjustment for various factors, including age, sex, allergies, and family history. The T/T genotype and the T allele of the c.-844T>C polymorphism were associated with increased occurrence of KC, while the C allele was associated with decreased KC occurrence. The G allele of the c.-671A>G polymorphism was associated with increased occurrence of FECD, while the A allele was associated with decreased FECD occurrence. The C/C-A/A combined genotype was associated with reduced risk of FECD, whereas the T/T-G/A combined genotype increased risk of KC. In conclusion, variability in the expression of the FAS and FASLG genes may be involved in the pathogenesis of KC and FECD.

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“…44 Interestingly, several authors have found evidence of increased apoptosis having a role in endothelial cell loss, as observed in FECD. 46,47 Furthermore, it was shown that the defense mechanism of FECD endothelium against oxidative stress-induced damage is impaired when compared with normal cells, 39,45,48,49 which is supported by the observed significant higher levels of (baseline) oxidative stressinduced damage, 43,45,48 and changes in endothelial cell morphology characteristic for oxidative stress. 50 These data suggest that chronic oxidative stress contributes to the pathophysiology of FECD, and that the decreased defense system renders FECD endothelial cells even more susceptible to oxidative stress-induced damage than normal cells already are.…”

Section: Pathophysiology Of Fecdmentioning

confidence: 90%

What does the future hold for the treatment of Fuchs endothelial dystrophy; will ‘keratoplasty’ still be a valid procedure?

Bruinsma

Tong

Melles

2013

Eye

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Fuchs endothelial corneal dystrophy (FECD) is a well recognized corneal disorder characterized by the presence of collagenous warts extending from Descemet membrane (guttae) and endothelial cellular dysfunction due to cell loss and/or degeneration. Because of the characteristic abnormal cell morphology as seen with specular microscopy as well as the limited regenerative capacity in vivo, the endothelial cells were considered to be 'dystrophic'. Hence, FECD is commonly managed by replacement of the endothelium with donor tissue by means of a penetrating or endothelial keratoplasty. The latter procedure has now been refined to the isolated transplantation of a donor Descemet membrane and its endothelium, referred to as Descemet membrane endothelial keratoplasty (DMEK). Unexpectedly, clinical observation made after DMEK seemed to challenge the current concept of the state of the endothelium in FECD; we actually observed an important role for the 'dystrophic' host endothelium in reendothelialization of the denuded DM, and subsequent corneal clearance. In addition, recent studies regarding the pathophysiology of FECD made us realize that the endothelial cells are not 'dystrophic' per se, but in the course of time may have acquired a dysfunction instead. This paper describes the rationale behind this new concept and based on this, discusses the possibilities for future, less invasive treatment modalities for FECD.

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p53-Regulated Increase in Oxidative-Stress–Induced Apoptosis in Fuchs Endothelial Corneal Dystrophy: A Native Tissue Model

Cited by 90 publications

References 14 publications

Menadione-Induced DNA Damage Leads to Mitochondrial Dysfunction and Fragmentation During Rosette Formation in Fuchs Endothelial Corneal Dystrophy

Menadione-Induced DNA Damage Leads to Mitochondrial Dysfunction and Fragmentation During Rosette Formation in Fuchs Endothelial Corneal Dystrophy

Polymorphisms of the Apoptosis-Related FAS and FAS Ligand Genes in Keratoconus and Fuchs Endothelial Corneal Dystrophy

What does the future hold for the treatment of Fuchs endothelial dystrophy; will ‘keratoplasty’ still be a valid procedure?

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