Induction of paraoxonase 1 and apolipoprotein A-I gene expression by aspirin** This study was supported by National Institutes of Health Grants RO1 HL-56353 and RO1 HL-069038. Published, JLR Papers in Press, June 2, 2008.

Low-dose aspirin therapy has become a standard in the treatment of cardiovascular diseases. Aspirin has been shown to inhibit atherosclerosis in mouse models. To determine the mechanisms by which aspirin might inhibit atherosclerosis, we incubated HEPG2 cells and rat primary hepatocytes with aspirin or salicylic acid and noted an increase in paraoxonase 1(PON1) activity in the medium, together with an induction of PON1 and apolipoprotein A-I (apoA-I) gene expression. Mice treated with aspirin also showed a 2-fold increase in plasma PON1 activity and a significant induction of both PON1 and apoA-I gene expression in the liver. The induction of the PON1 gene in cell culture was accompanied by an increase in arylhydrocarbon receptor (AhR) gene expression. Accordingly, aspirin treatment of AhR−/− animals failed to induce PON1 gene expression. We previously suggested that aspirin might be hydrolyzed by serum PON1, which could account for its short plasma half-life of 10 min. Taken together with the current studies, we suggest that the antiatherosclerotic effects of aspirin might be mediated by its hydrolytic product salicylate and that the induction of PON1 and apoA-I might be important in the cardioprotective effects of aspirin.

[1]  A. K. Pedersen,et al.  Systemic availability of acetylsalicylic acid in human subjects after oral ingestion of three different formulations. , 2009, Acta pharmacologica et toxicologica.

[2]  D. Shih,et al.  Adenovirus-Mediated Expression of Human Paraoxonase 3 Protects Against the Progression of Atherosclerosis in Apolipoprotein E–Deficient Mice , 2007, Arteriosclerosis, thrombosis, and vascular biology.

[3]  S. Deakin,et al.  HDL Oxidation Compromises its Influence on Paraoxonase-1 Secretion and its Capacity to Modulate Enzyme Activity , 2007, Arteriosclerosis, thrombosis, and vascular biology.

[4]  S. Parthasarathy,et al.  Aspirin is a substrate for paraoxonase-like activity: implications in atherosclerosis. , 2007, Atherosclerosis.

[5]  S. Barton.  Infectious diseases: New routes to antimalarials? , 2006, Nature Reviews Drug Discovery.

[6]  C. Chacon,et al.  PPARα activation potentiates AhR-induced CYP1A1 expression , 2005 .

[7]  D. Rader,et al.  Increased Atherosclerosis in Mice Lacking Apolipoprotein A-I Attributable to Both Impaired Reverse Cholesterol Transport and Increased Inflammation , 2005, Circulation research.

[8]  S. Parthasarathy,et al.  Oxidative inactivation of paraoxonase--implications in diabetes mellitus and atherosclerosis. , 2005, Biochimica et biophysica acta.

[9]  R. Eliakim,et al.  Paraoxonases (PONs) 1, 2, and 3 are expressed in human and mouse gastrointestinal tract and in Caco-2 cell line: selective secretion of PON1 and PON2. , 2005, Free radical biology & medicine.

[10]  H. Breddin,et al.  Aspirin and platelet function , 2004, Journal of thrombosis and haemostasis : JTH.

[11]  R. Barouki,et al.  Dietary Polyphenols Increase Paraoxonase 1 Gene Expression by an Aryl Hydrocarbon Receptor-Dependent Mechanism , 2004, Molecular and Cellular Biology.

[12]  S. Pervaiz.  Resveratrol: from grapevines to mammalian biology , 2003, FASEB journal : official publication of the Federation of American Societies for Experimental Biology.

[13]  B. La Du,et al.  Lactonase and lactonizing activities of human serum paraoxonase (PON1) and rabbit serum PON3. , 2003, Biochemical pharmacology.

[14]  J. Vane,et al.  The mechanism of action of aspirin. , 2003, Thrombosis research.

[15]  Kenneth K. Wu.  Aspirin and Other Cyclooxygenase Inhibitors: New Therapeutic Insights , 2003, Seminars in vascular medicine.

[16]  Robert Barouki,et al.  Opposite regulation of the human paraoxonase-1 gene PON-1 by fenofibrate and statins. , 2003, Molecular pharmacology.

[17]  R. James,et al.  Aspirin use is associated with higher serum concentrations of the anti-oxidant enzyme, paraoxonase-1 , 2003, Diabetologia.

[18]  A. Tward,et al.  Decreased Atherosclerotic Lesion Formation in Human Serum Paraoxonase Transgenic Mice , 2002, Circulation.

[19]  L. Ignarro,et al.  Potential cardioprotective actions of no-releasing aspirin , 2002, Nature Reviews Drug Discovery.

[20]  Rong Rong,et al.  Dietary oxidized fatty acids may enhance intestinal apolipoprotein A-I production. , 2002, Journal of lipid research.

[21]  H. Malonne,et al.  A reappraisal of the potential chemopreventive and chemotherapeutic properties of resveratrol. , 2001, Carcinogenesis.

[22]  H. Jakubowski.  Calcium-dependent Human Serum Homocysteine Thiolactone Hydrolase , 2000, The Journal of Biological Chemistry.

[23]  H. Ciolino,et al.  Dietary flavonols quercetin and kaempferol are ligands of the aryl hydrocarbon receptor that affect CYP1A1 transcription differentially. , 1999, The Biochemical journal.

[24]  V. Laudet,et al.  The Nuclear Receptors Peroxisome Proliferator-activated Receptor α and Rev-erbα Mediate the Species-specific Regulation of Apolipoprotein A-I Expression by Fibrates* , 1998, The Journal of Biological Chemistry.

[25]  D. Shih,et al.  Mice lacking serum paraoxonase are susceptible to organophosphate toxicity and atherosclerosis , 1998, Nature.

[26]  B. La Du,et al.  Paraoxonase inhibits high-density lipoprotein oxidation and preserves its functions. A possible peroxidative role for paraoxonase. , 1998, The Journal of clinical investigation.

[27]  T. Honjo,et al.  Human S mu binding protein-2 binds to the drug response element and transactivates the human apoA-I promoter: role of gemfibrozil. , 1998, Journal of lipid research.

[28]  A. Boulton,et al.  Serum paraoxonase activity, concentration, and phenotype distribution in diabetes mellitus and its relationship to serum lipids and lipoproteins. , 1995, Arteriosclerosis, thrombosis, and vascular biology.

[29]  S. Ghosh,et al.  Inhibition of NF-kappa B by sodium salicylate and aspirin. , 1994, Science.

[30]  J. Breslow,et al.  Characterization of the mouse apolipoprotein Apoa-1/Apoc-3 gene locus: genomic, mRNA, and protein sequences with comparisons to other species. , 1992, Genomics.

[31]  W. D. Mason,et al.  The pharmacokinetics of aspirin in rats and the effect of buffer , 1991, Journal of Pharmacokinetics and Biopharmaceutics.

[32]  I. Lipinska,et al.  High-density lipoproteins and atherosclerosis. , 1982, The New England journal of medicine.

[33]  J. Vane,et al.  Inhibition of prostaglandin synthesis as a mechanism of action for aspirin-like drugs. , 1971, Nature: New biology.

[34]  D. Praticò,et al.  Stabilization of advanced atherosclerosis in low-density lipoprotein receptor-deficient mice by aspirin. , 2006, Atherosclerosis.