title: Altered nitric oxide/cGMP platelet signaling pathway in platelets from patients with acute coronary syndromes.
abstract: This study was aimed at evaluating whether the nitric oxide (NO)/cyclic GMP (cGMP) signaling pathway is altered in platelets from patients with an acute coronary syndrome (unstable angina and acute myocardial infarction). We investigated 10 patients with unstable angina (UA), 14 with acute myocardial infarction (AMI) and 14 age and sex-matched healthy subjects. The serum markers of platelet activation (sP-selectin), inflammation (TNF-alpha and erythrocyte sedimentation rate), thrombotic state (fibrinogen) and plaque disruption were significantly higher in both UA and AMI patients compared to the healthy controls. In their platelets we assessed the cGMP levels in basal conditions and after stimulation with sodium nitroprusside (SNP), and performed Western blot analysis of homogenates to measure the expression of soluble guanylate cyclase isoforms. Basal levels of cGMP (pmol/10(10) platelets) were significantly higher in platelets from UA patients (1,097 +/- 111; p < 0.0001) and AMI (1,122 +/- 77; p < 0.0001) compared to those collected from healthy controls (497 +/- 80). The platelets of AMI patients exhibited a lack of cGMP increase after SNP stimulation in comparison with UA patients. The phosphorylation of upstream (Akt1 protein kinase alpha and endothelial NO synthase) and downstream (vasodilator-stimulated phosphoprotein, VASP) signaling proteins of the NO/cGMP pathway was investigated: serine phosphorylation in Akt1, eNOS and VASP was enhanced in platelets from UA and AMI patients when compared to controls. Furthermore, in AMI patients the inhibitors of guanylate cyclase and cGMP-dependent protein kinase did not revert the VASP phosphorylation. These data suggest that platelets from AMI patients are more resistant to SNP stimulation, not only as cGMP production, but also in terms of VASP activation. From these ex vivo results we hypothesize that the increased inflammatory state which often accompanies patients with cardiovascular diseases might promote a platelet preactivation resulting in their reduced sensitivity to NO.
authors.affiliation: Dipartimento di Genetica, Biologia e Biochimica (Sezione di Biochimica), University of Torino, Via Santena 5/bis, 10126, Turin, Italy. loredana.bergandi@unito.it
authors.forename: Loredana
authors.initials: L
authors.lastname: Bergandi
authors.forename: Marco
authors.initials: M
authors.lastname: Cordero
authors.forename: Matteo
authors.initials: M
authors.lastname: Anselmino
authors.forename: Gaetana
authors.initials: G
authors.lastname: Ferraro
authors.forename: Laura
authors.initials: L
authors.lastname: Ravera
authors.forename: Paola
authors.initials: P
authors.lastname: Dalmasso
authors.forename: Corrado
authors.initials: C
authors.lastname: Moiraghi
authors.forename: Gian Paolo
authors.initials: GP
authors.lastname: Trevi
authors.forename: Dario
authors.initials: D
authors.lastname: Ghigo
authors.forename: Amalia
authors.initials: A
authors.lastname: Bosia
authors.forename: Serena
authors.initials: S
authors.lastname: Bergerone
mesh_terms: D054058:Acute Coronary Syndrome / Q000378:metabolism*; D000368:Aged; D001792:Blood Platelets / Q000378:metabolism*; D016022:Case-Control Studies; D006152:Cyclic GMP / Q000378:metabolism*; D005260:Female; D006801:Humans; D008297:Male; D008875:Middle Aged; D009569:Nitric Oxide / Q000096:biosynthesis*; D015398:Signal Transduction
chemical_list: D009569:Nitric Oxide; D006152:Cyclic GMP
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