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
Por:
Vazquez-Meza, H, de Pina, MZ, Pardo, JP, Riveros-Rosas, H, Villalobos-Molina, R, Pina, E
Publicada:
30 may 2013
Resumen:
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 (Bt(2)cAMP)-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
Bt(2)cAMP-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
Bt(2)cAMP-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.
Filiaciones:
Univ Nacl Autonoma Mexico, Fac Med, Dept Bioquim, Mexico City 04510, DF, Mexico
Univ Nacl Autonoma Mexico, Fac Estudios Super Iztacala, Unidad Biomed, Mexico City 54090, DF, Mexico
|