The reactive aldehyde, acrolein, and factors associated with proliferative retinopathy




Kotchan, Eileen Dianne

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Acrolein, a reactive aldehyde, has been implicated in many disorders, including age-related macular degeneration (AMD) and diabetes. In this work, the effect of acrolein on ARPE-19 cells, a model for cells disrupted in both these disorders, was examined in terms of its effect on cell viability and the proangiogenic cytokines TGFbeta and VEGF, in two glucose concentrations 5.5mM and 18mM. It was found that acrolein decreased viable cell number in a concentration-dependent manner in both glucose concentrations, and that the effect of 50microM acrolein was significantly more pronounced in high glucose. Likewise, VEGF and TGFbeta1 and TGFbeta2 were increased by acrolein, and significantly more in high glucose. These effects were preventable by the co-treatment of the cells with 200microM N-benzylhydroxylamine (NBHA). It was found by the use of inhibitors that the changes induced by acrolein were at least partially due to a TGFbeta-mediated cell-signaling pathway using the regulatory signaling pathway protein Smad3, and that based on these observations, the effects of acrolein could be prevented in high and low glucose by blocking the TGFbeta receptor 1 (TRbeta1) or Smad 3. Analysis of eyes from normal and diabetic mice showed higher amounts of acrolein-modified proteins in diabetic eyes. Vitreous humor from normal and diabetic eyes likewise showed a higher acrolein-modified protein concentration in the diabetic sample. These studies suggest that the toxicity of acrolein to the cells and to the proangiogenic cytokine environment can be prevented by the sequestration of acrolein, or by blocking TGFbeta signaling through the TRbeta1. Our preliminary results show for the first time the presence of increased levels of acrolein-modified proteins both in human and animal diabetic eye samples. These results suggest that NBHA, or TRbeta1 blockade, i.e., SIS3 and SB431542, may prove to be pharmacologic agents for the prevention of acrolein-induced damage in AMD and diabetic retinopathy.


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acrolein, retinopathy, RPE, TGF beta



Integrative Biology