Platelet NAD(P)H-oxidase-generated ROS production regulates alphaIIbbeta3-integrin activation independent of the NO/cGMP pathway.
Platelets play a crucial role in the physiology of primary hemostasis and pathophysiologic processes such as arterial thrombosis. Accumulating evidence suggests a role of reactive oxygen species (ROSs) in platelet activation. Here we show that platelets activated with different agonists produced intracellular ROSs, which were reduced by reduced nicotinamide adenine dinucleotide (phosphate) (NAD(P)H) oxidase inhibitors and superoxide scavengers. In addition, we demonstrate that ROSs produced in platelets significantly affected alphaIIbbeta3 integrin activation but not alpha and dense granule secretion and platelet shape change. Thrombin-induced integrin alphaIIbbeta3 activation was significantly decreased after pretreatment of platelets with NAD(P)H oxidase inhibitors (diphenylene iodonium [DPI] [45% +/- 9%] and apocynin [43% +/- 11%]) and superoxide scavengers (tiron [60% +/- 9%] and Mn(III)tetrakis (1-methyl-4-pyridyl)porphyrin [MnTMPyP] [70% +/- 6%]). These inhibitors also reduced platelet aggregation and thrombus formation on collagen under high shear and achieved their effects independent of the nitric oxide/cyclic guanosine monophosphate (NO/cGMP) pathway.
Institut für Klinische Biochemie & Pathobiochemie, Josef Schneider Str 2, 97080 Würzburg, Germany.
Antonija Jurak
AJ
Begonja
Stepan
S
Gambaryan
Jörg
J
Geiger
Barsom
B
Aktas
Miroslava
M
Pozgajova
Bernhard
B
Nieswandt
Ulrich
U
Walter
D001792:Blood Platelets / Q000187:drug effects / Q000201:enzymology / Q000378:metabolism*; D006152:Cyclic GMP / Q000378:metabolism*; D004791:Enzyme Inhibitors / Q000494:pharmacology; D006801:Humans; D019255:NADPH Oxidases / Q000037:antagonists & inhibitors / Q000378:metabolism*; D009569:Nitric Oxide / Q000378:metabolism*; D019039:Platelet Glycoprotein GPIIb-IIIa Complex / Q000378:metabolism*; D017382:Reactive Oxygen Species / Q000378:metabolism*; D015398:Signal Transduction; D013481:Superoxides / Q000378:metabolism
D004791:Enzyme Inhibitors; D019039:Platelet Glycoprotein GPIIb-IIIa Complex; D017382:Reactive Oxygen Species; D013481:Superoxides; D009569:Nitric Oxide; D019255:NADPH Oxidases; D006152:Cyclic GMP