Pravastatin counteracts angiotensin II-induced upregulation and activation of NADPH oxidase at plasma membrane of human endothelial cells.
Endothelial dysfunction has been linked to reactive oxygen species (ROS) production by nicotinamide adenine dinucleotide phosphate reduced (NADPH) oxidase. Angiotensin II (ANG), which levels are elevated in some cardiovascular diseases, can stimulate this enzyme, whereas statins have been demonstrated pleiotropic effects related with the restoration of endothelial function. Therefore, our purpose was to study the mechanism of the possible beneficial effects of pravastatin on ANG-activated human umbilical vein endothelial cells (HUVEC). ANG induced an increase in the extracellular superoxide anion produced by NADPH oxidase but had no effect in the intracellular ROS production. Pravastatin, which alone did not have any effect on ROS production, totally blocked the stimulating effects of ANG when combined with it. These effects were not due to a direct action of ANG or pravastatin on the activity of NADPH oxidase measured in HUVEC lisates. On the contrary, the results correlated well with other effects of ANG: a Nox4 and p22phox upregulated expression and an enhanced Nox4 translocation to the cell membrane. All these effects were inhibited by pravastatin, which had no effect when incubated alone. These data reveal for the first time that pravastatin interrupts the signaling pathway activated by ANG that leads to an enhanced NADPH oxidase activity at the cell membrane of HUVEC. For that, pravastatin inhibits ANG-induced upregulation of catalytic NADPH oxidase subunits and blocks the migration of them to the endothelial cell membrane.
Alvarez
Ezequiel
E
Departamento de Medicina, Universidad de Santiago de Compostela and Servicio de Cardiología, Complejo Hospitalario Universitario de Santiago de Compostela, Spain. ezequiel.alvarez@usc.es
Rodiño-Janeiro
Bruno K
BK
Ucieda-Somoza
Rafael
R
González-Juanatey
José R
JR
D000804:Angiotensin II / Q000037:antagonists & inhibitors / Q000494:pharmacology*; D002462:Cell Membrane / Q000187:drug effects / Q000201:enzymology*; D002478:Cells, Cultured; D004730:Endothelium, Vascular / Q000166:cytology / Q000187:drug effects / Q000201:enzymology*; D004789:Enzyme Activation / Q000187:drug effects / Q000502:physiology; D006801:Humans; D019255:NADPH Oxidases / Q000037:antagonists & inhibitors* / Q000096:biosynthesis / Q000378:metabolism; D017035:Pravastatin / Q000494:pharmacology*; D015854:Up-Regulation / Q000187:drug effects / Q000502:physiology*
D000804:Angiotensin II; D019255:NADPH Oxidases; D017035:Pravastatin