Aspirin Increases Ferritin Synthesis in Endothelial Cells

A Novel Antioxidant Pathway

From the Department of Pharmacology and Toxicology, School of Pharmacy, Martin Luther University, Halle (Saale), Germany.

Correspondence to Dr Henning Schröder, School of Pharmacy, Martin Luther University, Wolfgang-Langenbeck-Str. 4, 06099 Halle (Saale), Germany. E-mail schroeder{at}pharmazie.uni-halle.de

Abstract—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.

Key Words: aspirin • ferritin • endothelial cell • gene expression • antioxidant defense mechanism

This article has been cited by other articles:

				A. A. PAWAR, A. VIKRAM, D. N. TRIPATHI, S. PADMANABHAN, P. RAMARAO, and G. JENA Modulation of Mitomycin C-induced Genotoxicity by Acetyl- and Thio- Analogues of Salicylic Acid In Vivo, March 1, 2009; 23(2): 303 - 307. [Abstract] [Full Text] [PDF]

				K. Erdmann, N. Grosser, K. Schipporeit, and H. Schroder The ACE Inhibitory Dipeptide Met-Tyr Diminishes Free Radical Formation in Human Endothelial Cells via Induction of Heme Oxygenase-1 and Ferritin J. Nutr., August 1, 2006; 136(8): 2148 - 2152. [Abstract] [Full Text] [PDF]

				G. Kojda Direct vasoprotection by aspirin: a significant bonus to antiplatelet activity? Cardiovasc Res, November 1, 2004; 64(2): 192 - 194. [Full Text] [PDF]

				J.L. Mehta, J. Chen, F. Yu, and D.Y. Li Aspirin inhibits ox-LDL-mediated LOX-1 expression and metalloproteinase-1 in human coronary endothelial cells Cardiovasc Res, November 1, 2004; 64(2): 243 - 249. [Abstract] [Full Text] [PDF]

				S. M Wasserman and J. N Topper Adaptation of the endothelium to fluid flow: in vitro analyses of gene expression and in vivo implications Vascular Medicine, February 1, 2004; 9(1): 35 - 45. [Abstract] [PDF]

				N. Grosser and H. Schroder Aspirin Protects Endothelial Cells From Oxidant Damage Via the Nitric Oxide-cGMP Pathway Arterioscler Thromb Vasc Biol, August 1, 2003; 23(8): 1345 - 1351. [Abstract] [Full Text] [PDF]

				S. Oberle, A. Abate, N. Grosser, A. Hemmerle, H. J. Vreman, P. A. Dennery, H. T. Schneider, D. Stalleicken, and H. Schroder Endothelial Protection by Pentaerithrityl Trinitrate: Bilirubin and Carbon Monoxide as Possible Mediators Experimental Biology and Medicine, May 1, 2003; 228(5): 529 - 534. [Abstract] [Full Text] [PDF]

				K. Prasad and P. Lee Suppression of Oxidative Stress as a Mechanism of Reduction of Hypercholesterolemic Atherosclerosis by Aspirin Journal of Cardiovascular Pharmacology and Therapeutics, March 1, 2003; 8(1): 61 - 69. [Abstract] [PDF]

				J. De Cristobal, A. Cardenas, I. Lizasoain, J. C. Leza, P. Fernandez-Tome, P. Lorenzo, and M. A. Moro Inhibition of Glutamate Release via Recovery of ATP Levels Accounts for a Neuroprotective Effect of Aspirin in Rat Cortical Neurons Exposed to Oxygen-Glucose Deprivation Stroke, January 1, 2002; 33(1): 261 - 267. [Abstract] [Full Text] [PDF]

				T. Polte, A. Abate, P. A. Dennery, and H. Schroder Heme Oxygenase-1 Is a cGMP-Inducible Endothelial Protein and Mediates the Cytoprotective Action of Nitric Oxide Arterioscler Thromb Vasc Biol, May 1, 2000; 20(5): 1209 - 1215. [Abstract] [Full Text] [PDF]

				A. Talbodec, N. Berkane, V. Blandin, J. P. Breittmayer, E. Ferrari, C. Frelin, and P. Vigne Aspirin and Sodium Salicylate Inhibit Endothelin ETA Receptors by an Allosteric Type of Mechanism Mol. Pharmacol., April 1, 2000; 57(4): 797 - 804. [Abstract] [Full Text]

				T. Stefanec Endothelial Apoptosis: Could It Have a Role in the Pathogenesis and Treatment of Disease? Chest, March 1, 2000; 117(3): 841 - 854. [Abstract] [Full Text] [PDF]

				A. Kagawa, H. Azuma, M. Akaike, Y. Kanagawa, and T. Matsumoto Aspirin Reduces Apolipoprotein(a) (Apo(a)) Production in Human Hepatocytes by Suppression of Apo(a) Gene Transcription J. Biol. Chem., November 26, 1999; 274(48): 34111 - 34115. [Abstract] [Full Text] [PDF]

				S. L. Hickenbottom, J. C. Grotta, R. Strong, L. A. Denner, J. Aronowski, and R. L. Macdonald Nuclear Factor-{kappa}B and Cell Death After Experimental Intracerebral Hemorrhage in Rats • Editorial Comment Stroke, November 1, 1999; 30 (11): 2472 - 2478. [Abstract] [Full Text] [PDF]

				T. Stefanec Circulating Apoptotic Endothelial Cells Blood, August 15, 1999; 94(4): 1482 - 1483. [Full Text] [PDF]

				B. de Valk and J. J. M. Marx Iron, Atherosclerosis, and Ischemic Heart Disease Arch Intern Med, July 26, 1999; 159(14): 1542 - 1548. [Abstract] [Full Text] [PDF]

				M. S. Wolin Novel Antioxidant Action of Aspirin May Contribute to Its Beneficial Cardiovascular Actions Circ. Res., May 19, 1998; 82(9): 1021 - 1022. [Full Text] [PDF]