title: Xanthine oxidoreductase is a critical mediator of cigarette smoke-induced endothelial cell DNA damage and apoptosis.
abstract: Cigarette smoke (CS) exposure is unquestionably the most frequent cause of emphysema in the United States. Accelerated pulmonary endothelial cell (EC) apoptosis is an early determinant of lung destruction in emphysema. One of the pathogenic causes of emphysema is an alveolar oxidant and antioxidant imbalance. The enzyme xanthine oxidoreductase (XOR) has been shown to be a source of reactive oxygen species (ROS) in a multitude of diseases (S. Sakao et al., FASEB J.21, 3640-3652; 2007). The contribution of XOR to CS-induced apoptosis is not well defined. Here we demonstrate that C57/bl6 mice exposed to CS have increased pulmonary XOR activity and protein levels compared to filtered-air-exposed controls. In addition, we demonstrate that primary pulmonary human lung microvascular endothelial cells exposed to cigarette smoke extract undergo increased rates of caspase-dependent apoptosis that are reliant on XOR activity, ROS production, and p53 function/expression. We also demonstrate that exogenous XOR is sufficient to increase p53 expression and induce apoptosis, suggesting that XOR is an upstream mediator of p53 in CS-induced EC apoptosis. Furthermore, we show that XOR activation results in DNA double-strand breaks that activate the enzyme ataxia telangiectasia mutated, which phosphorylates histone H2AX and upregulates p53. In conclusion, CS increases XOR expression, and the enzyme is both sufficient and necessary for p53 induction and CS-induced EC apoptosis.
authors: Division of Pulmonary and Critical Care Medicine, Department of Medicine.
authors: Bo S
authors: BS
authors: Kim
authors: Leonid
authors: L
authors: Serebreni
authors: Omar
authors: O
authors: Hamdan
authors: Lan
authors: L
authors: Wang
authors: Ahmad
authors: A
authors: Parniani
authors: Thomas
authors: T
authors: Sussan
authors: R
authors: R
authors: Scott Stephens
authors: Laurent
authors: L
authors: Boyer
authors: Mahendra
authors: M
authors: Damarla
authors: Paul M
authors: PM
authors: Hassoun
authors: Rachel
authors: R
authors: Damico
mesh_terms: D000818:Animals; D017209:Apoptosis / Q000187:drug effects; D053903:DNA Breaks, Double-Stranded / Q000187:drug effects; D004249:DNA Damage / Q000187:drug effects; D042783:Endothelial Cells / Q000166:cytology / Q000187:drug effects / Q000378:metabolism*; D005786:Gene Expression Regulation / Q000187:drug effects; D006801:Humans; D008168:Lung / Q000378:metabolism / Q000473:pathology; D051379:Mice; D010766:Phosphorylation / Q000187:drug effects; D011656:Pulmonary Emphysema / Q000201:enzymology / Q000378:metabolism* / Q000473:pathology; D017382:Reactive Oxygen Species / Q000378:metabolism; D012907:Smoking / Q000009:adverse effects*; D016159:Tumor Suppressor Protein p53 / Q000378:metabolism; D014968:Xanthine Dehydrogenase / Q000378:metabolism*
chemical_list: D017382:Reactive Oxygen Species; D016159:Tumor Suppressor Protein p53; D014968:Xanthine Dehydrogenase