Cigarette Smoke-Related Hydroquinone Induces Filamentous Actin Reorganization and Heat Shock Protein 27 Phosphorylation through p38 and Extracellular Signal-Regulated Kinase 1/2 in Retinal Pigment Epithelium

Abstract

Retinal pigment epithelium (RPE)-derived membranous debris named blebs, may accumulate and contribute to sub-RPE deposit formation, which is the earliest sign of age-related macular degeneration (AMD). Oxidative injury to the RPE might play a significant role in AMD. However, the underlying mechanisms are unknown. We previously reported that hydroquinone (HQ), a major pro-oxidant in cigarette smoke, foodstuff, and atmospheric pollutants, induces actin rearrangement and membrane blebbing in RPE cells as well as sub-RPE deposits in mice. Here, we show for the first time that phosphorylated Heat shock protein 27 (Hsp27), a key regulator of actin filaments dynamics, is up-regulated in RPE from patients with AMD. Also, HQ-induced nonlethal oxidative injury led to Hsp27mRNA up-regulation, dimer formation , and Hsp27 phosphorylation in ARPE-19 cells. Furthermore, we found that a cross talk between p38 and extracellular signal-regulated kinase (ERK) mediates HQ-induced Hsp27 phosphorylation and actin aggregate formation, revealing ERK as a novel upstream mediator of Hsp27 phosphorylation. Finally, we demonstrated that Hsp25, p38, and ERK phosphorylation are increased in aging C57BL/6 mice chronically exposed to HQ, whereas Hsp25 expression is decreased. Our data suggest that phosphorylated Hsp27 might be a key mediator in AMD and HQ-induced oxidative injury to the RPE, which may provide helpful insights into the early cellular events associated with actin reorganization and bleb formation involved in sub-RPE deposits formation relevant to the pathogenesis of AMD.

Effects of Hydroquinone on Cytoskeletal Organization and Intracellular Transport in Cultured Xenopus laevis Melanophores and Fibroblasts

“…Rearrangement of filamentous actin in cells treated with nonlethal doses of HQ has been reported. In retinal epithelium cells nonlethal oxidative injury with HQ induced blebbing and formation of actin aggregates mediated by phosporylation of Hsp27 [19,20]. Even if HQ has dramatic effects on microtubule organization and induces a loss of actin filaments in the present study, we cannot completely exclude that HQ exerts a direct effect on the molecular motors responsible for aggregation and dispersion.…”

Brimonidine Can Prevent In Vitro Hydroquinone Damage on Retinal Pigment Epithelium Cells and Retinal Müller Cells

“…[28][29][30][31][32] HQ has also been found in vitro and in animal models to affect gene expression of oxidative stress-related mediators and genes related to AMD pathogenesis. [33][34][35] HQ can reduce the activity of matrix metalloproteinase 2 (MMP-2) in vitro, 33 downregulate the monocyte chemoattractant protein 1 (MCP1), upregulate vascular endothelial growth factor (VEGF) and pigment epithelium-derived factor (PEDF) expression in vitro and in mice 34 , and upregulate the expression of heat shock protein 27 (Hsp-27) in mice and in vitro models. 35 In a rat model, it has been reported that after exposition to cigarette smoke or HQ supplemented in the rat's diet, the trial animals developed sub RPE deposits and Bruch's membrane thickening and deposits.…”

Angiotensin II–Induced MMP-2 Activity and MMP-14 and Basigin Protein Expression Are Mediated via the Angiotensin II Receptor Type 1–Mitogen-Activated Protein Kinase 1 Pathway in Retinal Pigment Epithelium

“…A substantial body of evidence suggests cross-talk between p38 and ERK MAPK cascades in a variety of cells 79 -82 including human RPE cells, as recently demonstrated. 83 Evidence was reported that p38 MAPK exerts a tonic inhibition on the ERK pathway that positively modulates p38 signaling under basal conditions in ARPE-19 cells. 83 The signaling events responsible for such cross-talk between p38 and ERK signaling cascades are poorly understood.…”

“…83 Evidence was reported that p38 MAPK exerts a tonic inhibition on the ERK pathway that positively modulates p38 signaling under basal conditions in ARPE-19 cells. 83 The signaling events responsible for such cross-talk between p38 and ERK signaling cascades are poorly understood. Cross-talk between parallel pathways of the MAPK cascades depends on a complex interplay involving kinases and phosphatases.…”