Abstract
Oxidative stress plays a major role in the pathophysiology of chronic inflammatory diseases, but it has also been linked to accelerated telomere shortening. Telomeres are specialized structures at the ends of linear chromosomes that protect these ends from degradation and fusion. Loss of telomeric DNA will result in telomere shortening and eventually cellular senescence. Research has shown that poly(ADP‐ribose)‐polymerase‐1 (PARP‐1) plays a role in telomere length regulation. We hypothesized that PARP‐1 plays a role in accelerated aging in chronic inflammatory diseases. In cultured human fibroblasts, effects of mild and strong inhibition of PARP‐1 under conditions of chronic oxidative stress, induced by tert‐butyl hydroperoxide (t‐BHP), were investigated. Fisetin (Fis), a flavonoid, was used as a mild inhibitor and Minocycline (Mino), an antibiotic, as a strong inhibitor of PARP‐1. Results indicated that t‐BHP and Mino alone induced a delay in cell growth and accelerated telomere shortening. However, when Mino was given in combination with t‐BHP, cells did not show a decrease in telomere length. Additionally, both Fis and Mino lowered the transcription of inflammation‐related genes in cells treated with t‐BHP. We conclude that PARP‐1 inhibition appears to be beneficial in conditions of chronic oxidative stress, but may be detrimental under relatively normal conditions.
Highlights
Chronic inflammatory diseases afflict millions of people across the world leading to a substantial social and economic burden
To determine whether chronic exposure of human fibroblasts (HF) cells to oxidative stress induces a faster rate of telomere shortening, we determined telomere length of HF cells exposed to 5 nM tert-butyl hydroperoxide (t-BHP)
Chronic fisetin treatment of HF at physiological concentrations resulted in shorter telomeres compared to control cells, indicating reduced telomere stability and enhanced biological aging of these cells
Summary
Chronic inflammatory diseases afflict millions of people across the world leading to a substantial social and economic burden. Telomeres are nucleoprotein structures at the end of chromosomes consisting of stretches of a repetitive DNA sequence, TTAGGG in humans. They prevent chromosomal ends from being recognized as double strand breaks and protect them from end-to-end fusions and degradation. Oxidative stress induces single-strand breaks both directly and indirectly. These are less efficiently repaired in telomeric DNA as compared to genomic DNA and, as a result, increase the rate of telomere shortening due to incomplete replication [10]
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