Aspirin increases ferritin synthesis in endothelial cells: a novel antioxidant pathway.

Aspirin has recently been shown to increase endothelial resistance to oxidative damage. However, the mechanism underlying aspirin-induced cytoprotection is still unknown. Using cultured cells, the present study investigates the effect of aspirin on the expression of ferritin, a cytoprotective protein that sequesters free cytosolic iron, the main catalyst of oxygen radical formation. In bovine pulmonary artery endothelial cells, aspirin at low antithrombotic concentrations (0.03 to 0.3 mmol/L) induced the synthesis of ferritin protein in a time- and concentration-dependent fashion up to 5-fold over basal levels, whereas ferritin H (heavy chain) mRNA remained unaltered. Aspirin-induced cytoprotection from hydrogen peroxide toxicity was mimicked by exogenous iron-free apoferritin but not iron-loaded ferritin, demonstrating the antioxidant function of newly synthesized ferritin under these conditions. Ferritin induction by aspirin was specific in that other nonsteroidal anti-inflammatory drugs such as salicylic acid, indomethacin, or diclofenac failed to alter ferritin protein levels. Aspirin-induced ferritin synthesis was abrogated in the presence of the iron chelator desferrioxamine, pointing to an interaction of aspirin with iron-responsive activation of ferritin translation. Together, our results suggest induction of ferritin as a novel mechanism by which aspirin may prevent endothelial injury in cardiovascular disease, eg, during atherogenesis.

Aspirin protects endothelial cells from oxidative stress--possible synergism with vitamin E.

A 24-h incubation with hydrogen peroxide (0.65 mM) markedly reduced viability of cultured endothelial cells. Preincubation with aspirin (3-30 microM) protected endothelial cells from hydrogen peroxide-induced toxicity and increased viability in a concentration-dependent fashion by up to 64% of control. A similar protection was observed with D-alpha-tocopherol acetate (vitamin E, 3-30 microM). The cytoprotective effects of aspirin and vitamin E against hydrogen peroxide were overadditive suggesting different mechanisms of antioxidant action. In agreement with this, cytotoxicity induced by iron, the main catalyst of oxygen radical formation, was substantially reduced by aspirin but not vitamin E. These results show that aspirin protects endothelial cells from oxidative stress possibly via binding or chelation of free cytosolic iron. Moreover, a combination of aspirin and vitamin E might be useful for the prevention of endothelial injury in cardiovascular disease, e.g. during atherogenesis.