Induction of paraoxonase 1 and apolipoprotein A-I gene expression by aspirin.
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.
Jaichander
Priscilla
P
Division of Cardiothoracic Surgery, Ohio State University Medical Center, Columbus, OH, USA.
Selvarajan
Krithika
K
Garelnabi
Mahdi
M
Parthasarathy
Sampath
S
D000818:Animals; D016632:Apolipoprotein A-I / Q000235:genetics* / Q000378:metabolism; D043303:Aryldialkylphosphatase / Q000235:genetics* / Q000378:metabolism; D001241:Aspirin / Q000494:pharmacology*; D045744:Cell Line, Tumor; D015971:Gene Expression Regulation, Enzymologic / Q000187:drug effects*; D020868:Gene Silencing; D022781:Hepatocytes / Q000187:drug effects / Q000378:metabolism; D006801:Humans; D051379:Mice; D034741:RNA, Small Interfering / Q000235:genetics / Q000378:metabolism; D051381:Rats; D018336:Receptors, Aryl Hydrocarbon / Q000378:metabolism; D012459:Salicylates / Q000494:pharmacology
D016632:Apolipoprotein A-I; D034741:RNA, Small Interfering; D018336:Receptors, Aryl Hydrocarbon; D012459:Salicylates; D043303:Aryldialkylphosphatase; D001241:Aspirin