Geldanamycin increases 4-hydroxynonenal (HNE)-induced cell death in human retinal pigment epithelial cells

Kaarniranta, Kai; Ryhänen, Tuomas; Karjalainen, Hannu M.; Lammi, Mikko J.; Suuronen, Tiina; Huhtala, Anne; Kontkanen, Matti; Teräsvirta, Markku; Uusitalo, Hannu; Salminen, Antero

doi:10.1016/j.neulet.2005.03.009

Cited by 47 publications

(34 citation statements)

References 33 publications

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“…Therefore, inhibition of inflammation occurring in the RPE has the potential to stop the disease formation or at least slow its progression. Our present data indicate that toxicity of HNE is higher in RPE cells stressed by serum starvation when compared to healthy ARPE-19 cells, in which the currently used 30 mM HNE did not induce significant cytotoxicity (Kaarniranta et al, 2005). We also demonstrated here that cell viability can be increased and the markers of inflammation decreased by the plant-derived polyphenol quercetin.…”

Section: Discussionsupporting

confidence: 63%

“…It is known that HNE prevents signaling through the transcription factor NF-kB (Kaarniranta et al, 2005;Page et al, 1999). Page et al examined with human monocytes and found that HNE could inhibit LPS, IL-1ß, and PMA (phorbol 12-myristate 13-acetate)-induced NF-kB activation by blocking the phosphorylation and thereby preventing the subsequent proteolysis of the inhibitory protein IkB (Page et al, 1999).…”

Section: Discussionmentioning

confidence: 99%

“…Protocols for using HNE, LPS, and quercetin were selected according to our previous and preliminary studies (Kaarniranta et al, 2005;Paimela et al, 2011) (Fig. 1).…”

Section: Cell Stimulationsmentioning

confidence: 99%

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Quercetin alleviates 4-hydroxynonenal-induced cytotoxicity and inflammation in ARPE-19 cells

Hytti

Piippo

Salminen

et al. 2015

Experimental Eye Research

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Section: Discussionsupporting

confidence: 63%

Section: Discussionmentioning

confidence: 99%

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Quercetin alleviates 4-hydroxynonenal-induced cytotoxicity and inflammation in ARPE-19 cells

Hytti

Piippo

Salminen

et al. 2015

Experimental Eye Research

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“…We have demonstrated that oxidative stress strongly induces HSP70 expression in RPE cells [5,44]. There is speculation that oxidative stress may increases permeabilization of lysosomes because of their content of redox-active iron and that may be one reason for the upregulation of the HSPs [45].…”

Section: Discussionmentioning

confidence: 83%

p62/sequestosome 1 as a regulator of proteasome inhibitor‐induced autophagy in human retinal pigment epithelial cells

KAARNIRANTA

2010

Acta Ophthalmologica

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Purpose:The pathogenesis of age-related macular degeneration involves impaired protein degradation in retinal pigment epithelial (RPE) cells. The ubiquitin-proteasome pathway and the lysosomal pathway including autophagy are the major proteolytic systems in eukaryotic cells. Prior to proteolysis, heat shock proteins (HSPs) attempt to refold stress-induced misfolded proteins and thus prevent the accumulation of cytoplasmic protein aggregates. Recently, p62/sequestosome 1 (p62) has been shown to be a key player linking the proteasomal and lysosomal clearance systems. In the present study, the functional roles of p62 and HSP70 were evaluated in conjunction with proteasome inhibitor-induced autophagy in human RPE cells . Methods: The p62, HSP70, and ubiquitin protein levels and localization were analyzed by western blotting and immunofluorescense. Confocal and transmission electron microscopy were used to detect cellular organelles and to evaluate the morphological changes. The p62 and HSP70 levels were modulated using RNA interference and overexpression techniques. Cell viability was measured by colorimetric assay. Results: Proteasome inhibition evoked the accumulation of perinuclear aggregates that strongly colocalized with p62 and HSP70. The p62 perinuclear accumulation was time-and concentration-dependent after MG-132 proteasome inhibitor loading. The silencing of p62, rather than Hsp70, evoked suppression of autophagy, when related to decreased LC3-II levels after bafilomycin treatment. In addition, the p62 silencing decreased the ubiquitination level of the perinuclear aggregates. Recently, we showed that hsp70 mRNA depletion increased cell death in ARPE-19 cells. Here, we demonstrate that p62 mRNA silencing has similar effects on cellular viability. Conclusions:Our findings open new avenues for understanding the mechanisms of proteolytic processes in retinal cells, and could be useful in the development of novel therapies targeting p62 and HSP70.Age-related macular degeneration (AMD) is the leading cause of blindness of elderly people in the developed countries. The disease affects the macula, which is located in the central area of the retina. Primarily, AMD is characterized by degeneration of the macular retinal pigment epithelial (RPE) cells [1]. The RPE cells take care of the health of rods and cones. Therefore, the degeneration and cell death of RPE cells cause secondary adverse effects on the neural cells, ultimately leading to visual loss. Chronic oxidative stress and inflammation are key factors evoking RPE degeneration and promoting the AMD process [2,3]. One hallmark of AMD is the accumulation of lysosomal lipofuscins, and extracellular drusens between RPE cells and Bruch's membrane. This cargo is a clear evidence of a disturbance in the cellular protein Correspondence to: Kai Kaarniranta, Department of Ophthalmology, University of Kuopio, P.O. Box 1627, 70211 Kuopio, Finland; Phone.: +358-17-162015; FAX: +358-17-162048; email: Kai.Kaarniranta@uef.fi clearance system in aged RPE cells [1]. Recently,...

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“…Furthermore, other inhibitors of Hsp90, radicicol and herbimycin A, which do not produce ROS, also yielded similar results, as did GA. This suggests that the elevated cytotoxicity found in the presence of GA in E47 cells is not due primarily to ROS production by GA itself but rather reflects an increased state of oxidative stress as a result of Hsp90 inhibition by GA. A recent study also showed that GA significantly increased cell death in retinal pigment epithelial cells treated with the lipid peroxidation product 4-hydroxynonenal, thus suggesting the protective role of Hsp90 in oxidative stress (Kaarniranta et al, 2005). Caspase 3 activity was not changed significantly in C34 cells upon treatment with GA, but it was elevated significantly in GA-treated E47 cells.…”

Section: Discussionmentioning

confidence: 93%

Geldanamycin, an Inhibitor of Hsp90, Potentiates Cytochrome P4502E1-Mediated Toxicity in HepG2 Cells

Dey

Cederbaum²

2006

J Pharmacol Exp Ther

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Cytochrome P450 2E1 (CYP2E1) potentiates oxidative stressmediated cell death. Heat shock proteins (Hsps) modulate the stability and function of numerous proteins. We examined the effect of geldanamycin (GA), an inhibitor of Hsp90, on CYP2E1-mediated toxicity in transfected HepG2 cells overexpressing CYP2E1 (E47 cells). Basal expression of CYP2E1 and Hsp90 was higher in E47 cells compared with control C34 cells, which do not express CYP2E1. Treatment with GA resulted in significant toxicity to E47 cells compared with C34 cells. An enhanced loss of E47 cell viability was also observed using two different inhibitors of Hsp90, herbimycin A and radicicol. Treatment of E47 cells with GA caused depletion of glutathione coupled to an increase in reactive oxygen species level and lipid peroxidation. These effects of GA were more pronounced in the E47 than the C34 cells. The antioxidants trolox and N-acetylcysteine prevented the increased reactive oxygen species accumulation and resultant loss of viability. GA caused increased caspase 3 activity and Annexin V staining in E47 cells, suggesting an apoptotic mode of cell death. A decrease in mitochondrial membrane potential was observed in GAtreated HepG2 cells, and mitochondrial permeability transition inhibitors prevented the cytotoxicity of GA. These results suggest that Hsp90 is protective against CYP2E1-dependent oxidant stress and loss of cell viability in HepG2 cells.

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Geldanamycin increases 4-hydroxynonenal (HNE)-induced cell death in human retinal pigment epithelial cells

Cited by 47 publications

References 33 publications

Quercetin alleviates 4-hydroxynonenal-induced cytotoxicity and inflammation in ARPE-19 cells

Quercetin alleviates 4-hydroxynonenal-induced cytotoxicity and inflammation in ARPE-19 cells

p62/sequestosome 1 as a regulator of proteasome inhibitor‐induced autophagy in human retinal pigment epithelial cells

Geldanamycin, an Inhibitor of Hsp90, Potentiates Cytochrome P4502E1-Mediated Toxicity in HepG2 Cells

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