1. Non-steroidal anti-inflammatory drugs activate NADPH oxidase in adipocytes and raise the H2O2 pool to prevent cAMP-stimulated protein kinase a activation and inhibit lipolysis
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Héctor Vázquez-Meza, Martha Zentella de Piña, Rafael Villalobos-Molina, Juan Pablo Pardo, Héctor Riveros-Rosas, and Enrique Piña
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Male ,medicine.medical_specialty ,Naproxen ,H2O2 ,Lipolysis ,Cyclic AMP-Dependent Protein Kinase Type II ,Piroxicam ,Aquaporins ,Biochemistry ,Internal medicine ,Acetylsalicylic acid ,medicine ,Adipocytes ,Animals ,Protein kinase A (PKA) ,Non-steroidal anti-inflammatory drug(s) (NSAID) ,Rats, Wistar ,Protein kinase A ,Molecular Biology ,Aspirin ,NADPH oxidase ,biology ,Chemistry ,Anti-Inflammatory Agents, Non-Steroidal ,NADPH Oxidases ,Hydrogen Peroxide ,Rats ,Enzyme Activation ,Endocrinology ,Non steroidal anti inflammatory ,biology.protein ,Silver Nitrate ,medicine.drug ,Nimesulide ,Research Article - Abstract
Background Non-steroidal anti-inflammatory drugs (NSAIDs) —aspirin, naproxen, nimesulide, and piroxicam— lowered activation of type II cAMP-dependent protein kinase A (PKA-II) in isolated rat adipocytes, decreasing adrenaline- and dibutyryl cAMP (Bt2cAMP)-stimulated lipolysis. The molecular bases of insulin-like actions of NSAID were studied. Results Based on the reported inhibition of lipolysis by H2O2, catalase was successfully used to block NSAID inhibitory action on Bt2cAMP-stimulated lipolysis. NSAID, at (sub)micromolar range, induced an H2O2 burst in rat adipocyte plasma membranes and in whole adipocytes. NSAID-mediated rise of H2O2 was abrogated in adipocyte plasma membranes by: diphenyleneiodonium, an inhibitor of NADPH oxidase (NOX); the NOX4 antibody; and cytochrome c, trapping the NOX-formed superoxide. These three compounds prevented the inhibition of Bt2cAMP-stimulated lipolysis by NSAIDs. Inhibition of aquaporin-mediated H2O2 transport with AgNO3 in adipocytes allowed NOX activation but prevented the lipolysis inhibition promoted by NSAID: i.e., once synthesized, H2O2 must reach the lipolytic machinery. Since insulin inhibits adrenaline-stimulated lipolysis, the effect of aspirin on isoproterenol-stimulated lipolysis in rat adipocytes was studied. As expected, isoproterenol-mediated lipolysis was blunted by both insulin and aspirin. Conclusions NSAIDs activate NOX4 in adipocytes to produce H2O2, which impairs cAMP-dependent PKA-II activation, thus preventing isoproterenol-activated lipolysis. H2O2 signaling in adipocytes is a novel and important cyclooxygenase-independent effect of NSAID.
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