title: Aspirin may promote mitochondrial biogenesis via the production of hydrogen peroxide and the induction of Sirtuin1/PGC-1α genes.
abstract: Based on the rapid hydrolysis of acetyl salicylic acid (ASA, Aspirin) to salicylic acid (SA), the ability of SA to form dihydroxy benzoic acid (DBA), and the latter's redox reactions to yield hydrogen peroxide (H(2)O(2)), we predicted that ASA may have the potential to induce Sirtuin1 (Sirt1) and its downstream effects. We observed that treatment of cultured liver cells with ASA resulted in the induction of Sirt1, peroxisome proliferator-activated receptor-gamma co-activator-1α (PGC-1α), and NAD(P)H quinone oxidoreductase 1 (Nqo1) genes. Paraoxonase 1 (PON1) and Aryl hydrocarbon receptor (AhR) siRNA transfections inhibited the induction of gene expressions by ASA suggesting the need for the acetyl ester hydrolysis and hydroxylation to DHBA. The latter also induced Sirt1, confirming the proposed pathway. As predicted, ASA and SA treatment resulted in the production of H(2)O(2), a known inducer of Sirt1 and confirmed in the current studies. More importantly, ASA treatment resulted in an increase in mitochondria as seen by tracking dyes. We suggest that DHBA, generated from ASA, via its oxidation/reduction reactions mediated by Nqo1 might be involved in the production of O(2)(-.) and H(2)O(2). As Sirt1 and PGC-1α profoundly affect mitochondrial metabolism and energy utilization, ASA may have therapeutic potential beyond its ability to inhibit cyclooxygenases.
authors.affiliation: Burnett School of Biomedical Sciences, College of Medicine, University of Central Florida, Orlando 32827, USA.
authors.forename: Pratibha
authors.initials: P
authors.lastname: Kamble
authors.forename: Krithika
authors.initials: K
authors.lastname: Selvarajan
authors.forename: Chandrakala
authors.initials: C
authors.lastname: Aluganti Narasimhulu
authors.forename: Mukesh
authors.initials: M
authors.lastname: Nandave
authors.forename: Sampath
authors.initials: S
authors.lastname: Parthasarathy
mesh_terms: D000818:Animals; D043303:Aryldialkylphosphatase / Q000235:genetics; D001241:Aspirin / Q000494:pharmacology*; D002478:Cells, Cultured; D005786:Gene Expression Regulation / Q000187:drug effects; D006360:Heat-Shock Proteins / Q000235:genetics; D056945:Hep G2 Cells; D022781:Hepatocytes / Q000187:drug effects / Q000378:metabolism; D006801:Humans; D006861:Hydrogen Peroxide / Q000378:metabolism*; D062385:Hydroxybenzoates / Q000378:metabolism; D051379:Mice; D008810:Mice, Inbred C57BL; D008930:Mitochondria, Liver / Q000187:drug effects* / Q000378:metabolism; D016660:NAD(P)H Dehydrogenase (Quinone) / Q000235:genetics; D010084:Oxidation-Reduction; D000071248:Peroxisome Proliferator-Activated Receptor Gamma Coactivator 1-alpha; D010975:Platelet Aggregation Inhibitors / Q000494:pharmacology; D018336:Receptors, Aryl Hydrocarbon / Q000235:genetics; D020156:Salicylic Acid / Q000494:pharmacology*; D056564:Sirtuin 1 / Q000235:genetics; D015534:Trans-Activators / Q000235:genetics; D014157:Transcription Factors / Q000235:genetics
chemical_list: D006360:Heat-Shock Proteins; D062385:Hydroxybenzoates; C486497:PPARGC1A protein, human; D000071248:Peroxisome Proliferator-Activated Receptor Gamma Coactivator 1-alpha; D010975:Platelet Aggregation Inhibitors; C485290:Ppargc1a protein, mouse; D018336:Receptors, Aryl Hydrocarbon; D015534:Trans-Activators; D014157:Transcription Factors; C009135:2,3-dihydroxybenzoic acid; D006861:Hydrogen Peroxide; D016660:NAD(P)H Dehydrogenase (Quinone); C447479:NQO1 protein, human; C491732:Nqo1 protein, mouse; D043303:Aryldialkylphosphatase; D056564:Sirtuin 1; D020156:Salicylic Acid; D001241:Aspirin